2022/01/27 更新

写真a

タケバヤシ ヒロヒデ
竹林 浩秀
TAKEBAYASHI Hirohide
所属
教育研究院 医歯学系 医学系列 教授
医学部 医学科 教授
医歯学総合研究科 生体機能調節医学専攻 感覚統合医学 教授
職名
教授
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外部リンク

学位

  • 博士(医学) ( 1999年3月   京都大学 )

研究キーワード

  • アストロサイト

  • 転写因子

  • オリゴデンドロサイト

  • ノックアウトマウス

  • 成体脳

  • グリア細胞

  • GABAニューロン

  • 神経細胞

  • 細胞分化

  • 神経幹細胞

  • Olig2

  • 運動ニューロン

  • タモキシフェン

  • 細胞系譜追跡実験

  • グルタミン酸

  • 放射状グリア細胞

  • ドメイン構造

  • PDGFα受容体

  • 前脳

  • CreER

  • 神経新生

  • エレクトロポレーション

  • 微小環境

  • 神経解剖学

  • ジストニア

  • 不随意運動

  • 小脳失調

研究分野

  • ライフサイエンス / 神経形態学

  • ライフサイエンス / 解剖学

  • ライフサイエンス / 神経科学一般

経歴(researchmap)

  • 新潟大学共用設備基盤センター   副センター長

    2017年 - 現在

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  • 新潟大学大学院 医歯学総合研究科   教授

    2011年 - 現在

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  • JSTさきがけ研究者(兼任)

    2010年 - 2014年

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  • 熊本大学大学院 生命科学研究部   Faculty of Life Sciences   准教授

    2008年 - 2011年

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  • 生理学研究所 分子生理研究系   Department of Molecular Physiology   助教

    2007年 - 2008年

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  • カリフォルニア大学サンフランシスコ校   ポスドク

    2004年 - 2006年

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  • 岡崎国立共同研究機構 生理学研究所   助手

    2002年

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  • 京都大学大学院 修了 京都大学博士(医学)

    1999年

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  • 京都大学医学部医学科 卒業   Faculty of Medicine, Department of Medical Science

    1995年

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経歴

  • 新潟大学   医学部 医学科   教授

    2011年10月 - 現在

  • 新潟大学   医歯学総合研究科 生体機能調節医学専攻 感覚統合医学   教授

    2011年10月 - 現在

委員歴

  • 第14回神経発生討論会 & 日韓共同シンポジウム   オーガナイザー  

    2021年3月   

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    団体区分:学協会

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  • Journal of Neurochemistry,   Senior Editor  

    2021年 - 現在   

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  • 第42回神経組織培養研究会   当番世話人  

    2020年11月   

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    団体区分:学協会

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  • 第124回日本解剖学会総会・全国学術集会(新潟)プログラム委員長  

    2019年3月   

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    団体区分:学協会

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  • 日本神経化学会   理事  

    2019年 - 現在   

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    団体区分:学協会

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  • 日本解剖学会   常任幹事  

    2019年 - 現在   

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    団体区分:学協会

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  • Neuro2019   実行委員  

    2019年   

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    団体区分:学協会

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  • 次世代脳プロジェクト「冬のシンポジウム」   優秀発表賞審査委員長  

    2019年   

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    団体区分:学協会

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  • 日韓神経発生共同シンポジウム(2国間交流事業) 日本側代表  

    2018年   

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    団体区分:学協会

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  • 日本神経化学会   優秀賞・奨励賞選考委員長  

    2017年 - 2019年   

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    団体区分:学協会

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  • 日本学術振興会   科学研究費委員会専門委員  

    2016年 - 2017年   

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  • Physiology and Pharmacology,   Editorial board  

    2015年 - 現在   

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    団体区分:学協会

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  • Journal of Neurochemistry,   Handling editor  

    2015年 - 2020年   

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    団体区分:学協会

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  • Neurochemical Research,   Editorial board  

    2015年 - 2019年   

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    団体区分:学協会

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  • 日本神経化学会   理事、シンポジウム企画委員長  

    2015年 - 2017年   

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    団体区分:学協会

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  • 日本学術振興会   特別研究員等審査会専門委員  

    2013年 - 2015年   

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    団体区分:学協会

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  • 日本学術振興会   国際事業委員会書面審査委員  

    2013年 - 2015年   

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    団体区分:学協会

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  • 日本解剖学会   評議員  

    2011年 - 現在   

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    団体区分:学協会

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  • 日本神経化学会   評議員  

    2010年 - 現在   

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    団体区分:学協会

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論文

  • Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression. 査読

    Bizen N, Bepari AK, Zhou L, Abe M, Sakimura K, Ono K, Takebayashi H

    Cell Death Differ, in press   2021年11月

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  • Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression. 査読 国際誌

    Anna Simankova, Norihisa Bizen, Sei Saitoh, Shinsuke Shibata, Nobuhiko Ohno, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi

    Glia   69 ( 11 )   2559 - 2574   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Oligodendrocytes form myelin sheaths that surround axons, contributing to saltatory conduction and proper central nervous system (CNS) function. Oligodendrocyte progenitor cells (OPCs) are generated during the embryonic stage and differentiate into myelinating oligodendrocytes postnatally. Ddx20 is a multifunctional, DEAD-box helicase involved in multiple cellular processes, including transcription, splicing, microRNA biogenesis, and translation. Although defects in each of these processes result in abnormal oligodendrocyte differentiation and myelination, the involvement of Ddx20 in oligodendrocyte terminal differentiation remains unknown. To address this question, we used Mbp-Cre mice to generate Ddx20 conditional knockout (cKO) mice to allow for the deletion of Ddx20 from mature oligodendrocytes. Mbp-Cre;Ddx20 cKO mice demonstrated small body sizes, behavioral abnormalities, muscle weakness, and short lifespans, with mortality by the age of 2 months old. Histological analyses demonstrated significant reductions in the number of mature oligodendrocytes and drastic reductions in the expression levels of myelin-associated mRNAs, such as Mbp and Plp at postnatal day 42. The number of OPCs did not change. A thin myelin layer was observed for large-diameter axons in Ddx20 cKO mice, based on electron microscopic analysis. A bromodeoxyuridine (BrdU) labeling experiment demonstrated that terminal differentiation was perturbed from ages 2 weeks to 7 weeks in the CNS of Mbp-Cre;Ddx20 cKO mice. The activation of mitogen-activated protein (MAP) kinase, which promotes myelination, was downregulated in the Ddx20 cKO mice based on immunohistochemical detection. These results indicate that Ddx20 is an essential factor for terminal differentiation of oligodendrocytes and maintenance of myelin gene expression.

    DOI: 10.1002/glia.24058

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/glia.24058

  • Cofilin Signaling in the CNS Physiology and Neurodegeneration. 査読 国際誌

    Jannatun Nayem Namme, Asim Kumar Bepari, Hirohide Takebayashi

    International journal of molecular sciences   22 ( 19 )   10727   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    All eukaryotic cells are composed of the cytoskeleton, which plays crucial roles in coordinating diverse cellular functions such as cell division, morphology, migration, macromolecular stabilization, and protein trafficking. The cytoskeleton consists of microtubules, intermediate filaments, and actin filaments. Cofilin, an actin-depolymerizing protein, is indispensable for regulating actin dynamics in the central nervous system (CNS) development and function. Cofilin activities are spatiotemporally orchestrated by numerous extra- and intra-cellular factors. Phosphorylation at Ser-3 by kinases attenuate cofilin's actin-binding activity. In contrast, dephosphorylation at Ser-3 enhances cofilin-induced actin depolymerization. Cofilin functions are also modulated by various binding partners or reactive oxygen species. Although the mechanism of cofilin-mediated actin dynamics has been known for decades, recent research works are unveiling the profound impacts of cofilin dysregulation in neurodegenerative pathophysiology. For instance, oxidative stress-induced increase in cofilin dephosphorylation is linked to the accumulation of tau tangles and amyloid-beta plaques in Alzheimer's disease. In Parkinson's disease, cofilin activation by silencing its upstream kinases increases α-synuclein-fibril entry into the cell. This review describes the molecular mechanism of cofilin-mediated actin dynamics and provides an overview of cofilin's importance in CNS physiology and pathophysiology.

    DOI: 10.3390/ijms221910727

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  • Reduction in miR‐219 expression underlies cellular pathogenesis of oligodendrocytes in a mouse model of Krabbe disease 査読

    Naoko Inamura, Shinji Go, Takashi Watanabe, Hiroshi Takase, Nobuyuki Takakura, Atsuo Nakayama, Hirohide Takebayashi, Junko Matsuda, Yasushi Enokido

    Brain Pathology   e12951   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/bpa.12951

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bpa.12951

  • Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice. 査読 国際誌

    Naofumi Ito, M Asrafuzzaman Riyadh, Shah Adil Ishtiyaq Ahmad, Satoko Hattori, Yonehiro Kanemura, Hiroshi Kiyonari, Takaya Abe, Yasuhide Furuta, Yohei Shinmyo, Naoko Kaneko, Yuki Hirota, Giuseppe Lupo, Jun Hatakeyama, Felemban Athary Abdulhaleem M, Mohammad Badrul Anam, Masahiro Yamaguchi, Toru Takeo, Hirohide Takebayashi, Minoru Takebayashi, Yuichi Oike, Naomi Nakagata, Kenji Shimamura, Michael J Holtzman, Yoshiko Takahashi, Francois Guillemot, Tsuyoshi Miyakawa, Kazunobu Sawamoto, Kunimasa Ohta

    Science translational medicine   13 ( 587 )   easy7896   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The lateral ventricle (LV) is flanked by the subventricular zone (SVZ), a neural stem cell (NSC) niche rich in extrinsic growth factors regulating NSC maintenance, proliferation, and neuronal differentiation. Dysregulation of the SVZ niche causes LV expansion, a condition known as hydrocephalus; however, the underlying pathological mechanisms are unclear. We show that deficiency of the proteoglycan Tsukushi (TSK) in ependymal cells at the LV surface and in the cerebrospinal fluid results in hydrocephalus with neurodevelopmental disorder-like symptoms in mice. These symptoms are accompanied by altered differentiation and survival of the NSC lineage, disrupted ependymal structure, and dysregulated Wnt signaling. Multiple TSK variants found in patients with hydrocephalus exhibit reduced physiological activity in mice in vivo and in vitro. Administration of wild-type TSK protein or Wnt antagonists, but not of hydrocephalus-related TSK variants, in the LV of TSK knockout mice prevented hydrocephalus and preserved SVZ neurogenesis. These observations suggest that TSK plays a crucial role as a niche molecule modulating the fate of SVZ NSCs and point to TSK as a candidate for the diagnosis and therapy of hydrocephalus.

    DOI: 10.1126/scitranslmed.aay7896

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  • Retrograde gene transfer into neural pathways mediated by adeno-associated virus (AAV)-AAV receptor interaction. 査読 国際誌

    Hiromi Sano, Kenta Kobayashi, Nozomu Yoshioka, Hirohide Takebayashi, Atsushi Nambu

    Journal of neuroscience methods   345   108887 - 108887   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Viral vector systems delivering transgenes in the retrograde direction through axons to neural cell bodies are powerful experimental tools for the functional analysis of specific neural pathways. Generally, the efficiency of viral vector-mediated retrograde gene transfer depends on the expression of requisite viral receptors in neural pathways projecting to the viral vector-injected regions. This is known as viral tropism and can limit the utility of retrograde viral vectors. The adeno-associated virus (AAV) vector has become an increasingly popular platform for gene delivery to neural cells in vivo, and it is therefore meaningful to develop a new type of retrograde gene transfer approach based on a tropism-free AAV vector system. NEW METHOD: The wild-type or mutant receptor gene of AAV was expressed to mitigate AAV tropism. RESULTS: Efficient AAV vector-mediated retrograde gene transfer was observed in diverse neural pathways by expression of the AAV receptor (AAVR) gene. Moreover, the expression of a minimal mutant of AAVR (miniAAVR), which maintains binding potential to AAV, demonstrated efficient retrograde gene expression comparable to that of AAVR. COMPARISON WITH EXISTING METHODS: The utility of existing AAV vector-mediated retrograde gene delivery methods is sometimes limited by tropism. Our newly developed AAV-AAVR and AAV-miniAAVR interaction approaches enabled efficient retrograde gene transfer into various neural pathways by mitigating tropism. CONCLUSIONS: AAV-AAVR and AAV-miniAAVR interaction approaches enabled us to induce efficient retrograde gene expression in targeted neural pathways and provide a powerful tool for analyzing specific neural pathways.

    DOI: 10.1016/j.jneumeth.2020.108887

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  • Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury. 査読 国際誌

    Masaki Ueno, Yuka Nakamura, Hiroshi Nakagawa, Jesse K Niehaus, Mari Maezawa, Zirong Gu, Atsushi Kumanogoh, Hirohide Takebayashi, Qing Richard Lu, Masahiko Takada, Yutaka Yoshida

    Cerebral cortex (New York, N.Y. : 1991)   30 ( 11 )   5702 - 5716   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.

    DOI: 10.1093/cercor/bhaa142

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  • Oligodendrogenesis and Myelin Formation in the Forebrain Require Platelet-derived Growth Factor Receptor-alpha. 査読 国際誌

    Takeru Hamashima, Yoko Ishii, Linh Quang Nguyen, Noriko Okuno, Yang Sang, Takako Matsushima, Yoichi Kurashige, Hirohide Takebayashi, Hisashi Mori, Toshihiko Fujimori, Seiji Yamamoto, Masakiyo Sasahara

    Neuroscience   436   11 - 26   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The platelet-derived growth factor receptor-α (PDGFRα) principally mediates growth factor signals in oligodendroglial progenitors and is involved in oligodendrogenesis and myelinogenesis in the developing spinal cord. However, the role of PDGFRα in the developing forebrain remains relatively unknown. We established a conditional knockout mouse for the Pdgfra gene (N-PRα-KO) using a Nestin promoter/enhancer-driven Cre recombinase and examined forebrain development. The expression of PDGFRα was efficiently suppressed in the Olig2+ cells in N-PRα-KO mice. In these mice, Olig2+ cells were slightly decreased during embryonic periods. The decrease was particularly striking during the postnatal period. The commitment of Pdgfra-inactivated Olig2+ cells to Sox10+ oligodendroglial-lineage was largely suppressed. Surviving Olig2+ cells and Sox10+ cells were distributed widely in the N-PRα-KO mouse brain, similarly to those in control mice until the early neonatal period. After that, these cells were drastically depleted in the forebrain during the second postnatal week. The brains of N-PRα-KO mice were severely hypomyelinated, and these mice died on approximately P17 with motor disturbances. Disturbed axonal fibers and extensively aberrant vascular formations appeared in the postnatal N-PRα-KO mouse brains. After the defective PDGFRα signal in the forebrain, these phenotypes were clearly different from those in the spinal cord that showed defective populations expansion and migration of oligodendroglial lineage and premature myelination, as previously described. In contrast, areas of severe hypomyelination were common to both anatomical sites. PDGFRα was critically involved in the myelination of the forebrain and may differently regulate oligodendroglial lineage between the forebrain and spinal cord.

    DOI: 10.1016/j.neuroscience.2020.04.001

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  • Disruption of dystonin in Schwann cells results in late-onset neuropathy and sensory ataxia. 査読 国際誌

    Masao Horie, Nozomu Yoshioka, Satoshi Kusumi, Hiromi Sano, Masayuki Kurose, Izumi Watanabe-Iida, Ibrahim Hossain, Satomi Chiken, Manabu Abe, Kensuke Yamamura, Kenji Sakimura, Atsushi Nambu, Masahiro Shibata, Hirohide Takebayashi

    Glia   68 ( 11 )   2330 - 2344   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia-like movement and ataxia with sensory degeneration. Dst is expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, the Dst-expressing cell type(s) for dt phenotypes have not been well characterized. To address the questions whether the disruption of Dst in Schwann cells induces movement disorders and how much impact does it have on dt phenotypes, we generated Dst conditional knockout (cKO) mice using P0-Cre transgenic mice and Dst gene trap mice. First, we assessed the P0-Cre transgene-dependent Cre recombination using tdTomato reporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In the Dst cKO mice, Dst mRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype of Dst cKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity in Dst cKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS of Dst cKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate that Dst is important for normal PNS myelin organization and Dst disruption in Schwann cells induces late-onset neuropathy and sensory ataxia. MAIN POINTS: Dystonin (Dst) disruption in Schwann cells results in late-onset neuropathy and sensory ataxia. Dst in Schwann cells is important for normal myelin organization in the peripheral nervous system.

    DOI: 10.1002/glia.23843

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  • Diverse dystonin gene mutations cause distinct patterns of Dst isoform deficiency and phenotypic heterogeneity in Dystonia musculorum mice. 査読 国際誌

    Nozomu Yoshioka, Yudai Kabata, Momona Kuriyama, Norihisa Bizen, Li Zhou, Dang M Tran, Masato Yano, Atsushi Yoshiki, Tatsuo Ushiki, Thomas J Sproule, Riichiro Abe, Hirohide Takebayashi

    Disease models & mechanisms   13 ( 5 )   mm041608   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Loss-of-function mutations in dystonin (DST) can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, DST-related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single DST locus produces at least three major DST isoforms: DST-a (neuronal isoform), DST-b (muscular isoform) and DST-e (epithelial isoform). Dystonia musculorum (dt) mice, which have mutations in Dst, were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the phenotypic heterogeneity of DST-related diseases, we investigated two mutant strains with different mutations: a spontaneous Dst mutant (Dstdt-23Rbrc mice) and a gene-trap mutant (DstGt mice). The Dstdt-23Rbrc allele possesses a nonsense mutation in an exon shared by all Dst isoforms. The DstGt allele is predicted to inactivate Dst-a and Dst-b isoforms but not Dst-e There was a decrease in the levels of Dst-a mRNA in the neural tissue of both Dstdt-23Rbrc and DstGt homozygotes. Loss of sensory and autonomic nerve ends in the skin was observed in both Dstdt-23Rbrc and DstGt mice at postnatal stages. In contrast, Dst-e mRNA expression was reduced in the skin of Dstdt-23Rbrc mice but not in DstGt mice. Expression levels of Dst proteins in neural and cutaneous tissues correlated with Dst mRNAs. Because Dst-e encodes a structural protein in hemidesmosomes (HDs), we performed transmission electron microscopy. Lack of inner plaques and loss of keratin filament invasions underneath the HDs were observed in the basal keratinocytes of Dstdt-23Rbrc mice but not in those of DstGt mice; thus, the distinct phenotype of the skin of Dstdt-23Rbrc mice could be because of failure of Dst-e expression. These results indicate that distinct mutations within the Dst locus can cause different loss-of-function patterns among Dst isoforms, which accounts for the heterogeneous neural and skin phenotypes in dt mice and DST-related diseases.

    DOI: 10.1242/dmm.041608

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  • The fornix acts as a permissive corridor for septal neuron migration beyond the diencephalic-telencephalic boundary. 査読 国際誌

    Keisuke Watanabe, Hirohide Takebayashi, Noboru Sato

    Scientific reports   10 ( 1 )   8315 - 8315   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuronal migration is essential for constructing functional neural networks. Two posterior septal (PS) nuclei, the triangular septal nucleus and bed nuclei of the anterior commissure, are involved in fear and anxiety. During development, glutamatergic PS neurons undergo long-distance rostrodorsal migration from the thalamic eminence (TE) of the diencephalon, then settle in the caudalmost telencephalon. However, the developmental behavior of PS neurons and the guidance structures facilitating their migration remain unknown. We previously demonstrated the migration of PS neurons along the fornix, a major efferent pathway from the hippocampal formation. Here, we show that the postcommissural fornix is essential for PS neuron migration which is largely confined to its axonal tract, which grows in the opposite direction as PS neuron migration. Fornical axons reach the TE prior to initiation of PS neuron rostrodorsal migration. Ectopic expression of Semaphorin 3 A in the dorsomedial cortex resulted in defective fornix formation. Furthermore, loss of the postcommissural fornix stalled PS neuron migration resulting in abnormal accumulation near their origin. This suggests that PS neurons utilize the postcommissural fornix as a permissive corridor during migration beyond the diencephalic-telencephalic boundary. This axonal support is essential for the functional organization of the heterogeneous septal nuclear complex.

    DOI: 10.1038/s41598-020-65284-7

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  • Reciprocal connectivity between secondary auditory cortical field and amygdala in mice. 査読 国際誌

    Hiroaki Tsukano, Xubin Hou, Masao Horie, Hiroki Kitaura, Nana Nishio, Ryuichi Hishida, Kuniyuki Takahashi, Akiyoshi Kakita, Hirohide Takebayashi, Sayaka Sugiyama, Katsuei Shibuki

    Scientific reports   9 ( 1 )   19610 - 19610   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent studies have examined the feedback pathway from the amygdala to the auditory cortex in conjunction with the feedforward pathway from the auditory cortex to the amygdala. However, these connections have not been fully characterized. Here, to visualize the comprehensive connectivity between the auditory cortex and amygdala, we injected cholera toxin subunit b (CTB), a bidirectional tracer, into multiple subfields in the mouse auditory cortex after identifying the location of these subfields using flavoprotein fluorescence imaging. After injecting CTB into the secondary auditory field (A2), we found densely innervated CTB-positive axon terminals that were mainly located in the lateral amygdala (La), and slight innervations in other divisions such as the basal amygdala. Moreover, we found a large number of retrogradely-stained CTB-positive neurons in La after injecting CTB into A2. When injecting CTB into the primary auditory cortex (A1), a small number of CTB-positive neurons and axons were visualized in the amygdala. Finally, we found a near complete absence of connections between the other auditory cortical fields and the amygdala. These data suggest that reciprocal connections between A2 and La are main conduits for communication between the auditory cortex and amygdala in mice.

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  • Olig2 regulates terminal differentiation and maturation of peripheral olfactory sensory neurons. 査読

    Wang YZ, Fan H, Ji Y, Reynolds K, Gu R, Gan Q, Yamagami T, Zhao T, Hamad S, Bizen N, Takebayashi H, Chen Y, Wu S, Pleasure D, Lam K, Zhou CJ

    Cellular and molecular life sciences : CMLS   2019年11月

  • Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model. 査読 国際誌

    Mika Terumitsu-Tsujita, Hiroki Kitaura, Ikuo Miura, Yuji Kiyama, Fumiko Goto, Yoshiko Muraki, Shiho Ominato, Norikazu Hara, Anna Simankova, Norihisa Bizen, Kazuhiro Kashiwagi, Takuhiro Ito, Yasuko Toyoshima, Akiyoshi Kakita, Toshiya Manabe, Shigeharu Wakana, Hirohide Takebayashi, Hironaka Igarashi

    Journal of neurochemistry   154 ( 1 )   25 - 40   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development.

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  • Acute spatial spread of NO-mediated potentiation during hindpaw ischemia in mice. 査読 国際誌

    Onishi T, Watanabe T, Sasaki M, Kamiya Y, Horie M, Tsukano H, Hishida R, Kohno T, Takebayashi H, Baba H, Shibuki K

    The Journal of physiology   597 ( 13 )   3441 - 3455   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1113/JP277615

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  • Feedback inhibition derived from the posterior parietal cortex regulates the neural properties of the mouse visual cortex. 査読

    Hishida R, Horie M, Tsukano H, Tohmi M, Yoshitake K, Meguro R, Takebayashi H, Yanagawa Y, Shibuki K

    The European journal of neuroscience   50   2970 - 2987   2019年4月

  • Direct Relay Pathways from Lemniscal Auditory Thalamus to Secondary Auditory Field in Mice. 査読 国際誌

    Shinpei Ohga, Hiroaki Tsukano, Masao Horie, Hiroki Terashima, Nana Nishio, Yamato Kubota, Kuniyuki Takahashi, Ryuichi Hishida, Hirohide Takebayashi, Katsuei Shibuki

    Cerebral cortex (New York, N.Y. : 1991)   28 ( 12 )   4424 - 4439   2018年12月

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    記述言語:英語  

    Tonotopy is an essential functional organization in the mammalian auditory cortex, and its source in the primary auditory cortex (A1) is the incoming frequency-related topographical projections from the ventral division of the medial geniculate body (MGv). However, circuits that relay this functional organization to higher-order regions such as the secondary auditory field (A2) have yet to be identified. Here, we discovered a new pathway that projects directly from MGv to A2 in mice. Tonotopy was established in A2 even when primary fields including A1 were removed, which indicates that tonotopy in A2 can be established solely by thalamic input. Moreover, the structural nature of differing thalamocortical connections was consistent with the functional organization of the target regions in the auditory cortex. Retrograde tracing revealed that the region of MGv input to a local area in A2 was broader than the region of MGv input to A1. Consistent with this anatomy, two-photon calcium imaging revealed that neuronal responses in the thalamocortical recipient layer of A2 showed wider bandwidth and greater heterogeneity of the best frequency distribution than those of A1. The current study demonstrates a new thalamocortical pathway that relays frequency information to A2 on the basis of the MGv compartmentalization.

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  • Locally induced neuronal synchrony precisely propagates to specific cortical areas without rhythm distortion 査読

    Haruo Toda, Keisuke Kawasaki, Sho Sato, Masao Horie, Kiyoshi Nakahara, Asim K. Bepari, Hirohito Sawahata, Takafumi Suzuki, Haruo Okado, Hirohide Takebayashi, Isao Hasegawa

    Scientific Reports   8 ( 1 )   7678   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Publishing Group  

    Propagation of oscillatory spike firing activity at specific frequencies plays an important role in distributed cortical networks. However, there is limited evidence for how such frequency-specific signals are induced or how the signal spectra of the propagating signals are modulated during across-layer (radial) and inter-areal (tangential) neuronal interactions. To directly evaluate the direction specificity of spectral changes in a spiking cortical network, we selectively photostimulated infragranular excitatory neurons in the rat primary visual cortex (V1) at a supra-threshold level with various frequencies, and recorded local field potentials (LFPs) at the infragranular stimulation site, the cortical surface site immediately above the stimulation site in V1, and cortical surface sites outside V1. We found a significant reduction of LFP powers during radial propagation, especially at high-frequency stimulation conditions. Moreover, low-gamma-band dominant rhythms were transiently induced during radial propagation. Contrastingly, inter-areal LFP propagation, directed to specific cortical sites, accompanied no significant signal reduction nor gamma-band power induction. We propose an anisotropic mechanism for signal processing in the spiking cortical network, in which the neuronal rhythms are locally induced/modulated along the radial direction, and then propagate without distortion via intrinsic horizontal connections for spatiotemporally precise, inter-areal communication.

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  • Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype. 査読 国際誌

    Li Zhou, M Ibrahim Hossain, Maya Yamazaki, Manabu Abe, Rie Natsume, Kohtaro Konno, Shun Kageyama, Masaaki Komatsu, Masahiko Watanabe, Kenji Sakimura, Hirohide Takebayashi

    Journal of neurochemistry   147 ( 4 )   557 - 572   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purkinje cell degeneration (pcd) was first identified in a spontaneous mouse mutant showing cerebellar ataxia. In addition to cerebellar Purkinje cells (PCs), retinal photoreceptors, mitral cells in the olfactory bulb, and a discrete subpopulation of thalamic neurons also degenerate in the mutant brains. The gene responsible for the pcd mutant is Nna1, also known as ATP/GTP binding protein 1 or cytosolic carboxypeptidase-like 1, which encodes a zinc carboxypeptidase protein. To investigate pathogenesis of the pcd mutation in detail, we generated a conditional Nna1 allele targeting the carboxypeptidase domain at C-terminus. After Cre recombination and heterozygous crossing, we generated Nna1 knockout (KO) mice and found that the Nna1 KO mice began to show cerebellar ataxia at postnatal day 20 (P20). Most PCs degenerated until 4-week-old, except lobule X. Activated microglia and astrocytes were also observed in the Nna1 KO cerebellum. In the mutant brain, the Nna1 mRNA level was dramatically reduced, suggesting that nonsense-mediated mRNA decay occurs in it. Since the Nna1 protein acts as a de-glutamatase on the C-terminus of α-tubulin and β-tubulin, increased polyglutamylated tubulin was detected in the Nna1 KO cerebellum. In addition, the endoplasmic reticulum stress marker, C/EBP homologous protein (CHOP), was up-regulated in the mutant PCs. We report the generation of a functional Nna1 conditional allele and possible mechanisms of PC death in the Nna1 KO in the cerebellum. OPEN PRACTICES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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  • Developmental defects and aberrant accumulation of endogenous psychosine in oligodendrocytes in a murine model of Krabbe disease. 査読

    Inamura N, Kito M, Go S, Kishi S, Hosokawa M, Asai K, Takakura N, Takebayashi H, Matsuda J, Enokido Y

    Neurobiology of disease   120   51 - 62   2018年8月

  • Diencephalic progenitors contribute to the posterior septum through rostral migration along the hippocampal axonal pathway. 査読 国際誌

    Watanabe K, Irie K, Hanashima C, Takebayashi H, Sato N

    Scientific reports   8 ( 1 )   11728 - 11728   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Origin of Oligodendrocytes in the Vertebrate Optic Nerve: A Review 査読

    Katsuhiko Ono, Yukie Hirahara, Hitoshi Gotoh, Tadashi Nomura, Hirohide Takebayashi, Hisao Yamada, Kazuhiro Ikenaka

    Neurochemical Research   43 ( 1 )   186 - 194   2018年1月

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    記述言語:英語   出版者・発行元:Springer New York LLC  

    One of the unsolved problems in the research field of oligodendrocyte (OL) development has been the site(s) of origin of optic nerve OLs and its precursor cells (OPCs). It is generally accepted that OLs in the optic nerve are derived from the brain, and thus optic nerve OLs are immigrant cells. We previously demonstrated the brain origin of optic nerve OPCs in chick embryos. However, the site of optic nerve OPC origin has not been examined experimentally in developing rodents for the past two decades. We have recently reported that optic nerve OPCs in mice arise in the preoptic area by E12.5 and gradually migrate caudally and enter the optic nerve. These OPCs give rise to myelinating OLs in the optic nerve in the postnatal or adult stages. Surprisingly, there are species differences with respect to the origin of optic nerve OPCs between chicks and mice. Here, we summarize the site of OPC origin in the optic nerve based on our own previous and recent results, and discuss possible mechanisms underlying these species differences.

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  • Reduced Proliferation of Oligodendrocyte Progenitor Cells in the Postnatal Brain of Dystonia Musculorum Mice 査読

    M. Ibrahim Hossain, Masao Horie, Hirohide Takebayashi

    Neurochemical Research   43 ( 1 )   92 - 100   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer New York LLC  

    Dystonia musculorum (dt) mice show sensory neurodegeneration and movement disorder, such as dystonia and cerebellar ataxia. The causative gene Dystonin (Dst) encodes a cytoskeleton linker protein. Although sensory neurodegeneration has been well studied, glial cell responses in the central nervous system (CNS) are poorly understood. Here, we investigated cell proliferation in the CNS of DstGt homozygous mice using newly generated in situ hybridization (ISH) probes—Ki-67 and proliferating cell nuclear antigen (PCNA) probes—both of which effectively detect proliferating cells. We found that Ki-67-positive cells were significantly decreased in the corpus callosum and thalamus of dt brain at postnatal day 21 (P21). There is a similar but not significant tendency at postnatal day 14 (P14) in the dt brain. We also confirmed the reduced proliferation by PCNA ISH and Ki-67 immunohistochemistry. Double staining with cell-type-specific markers revealed that proliferating cells are oligodendrocyte progenitor cells (OPCs) in both wild-type and dt brain. We also observed a reduced number of Olig2-positive cells in the corpus callosum of DstGt homozygous mice at P21, indicating that reduced proliferation resulted in a reduced number of OPCs. Our data indicate that OPCs proliferation is reduced in the dt mouse brain at the postnatal stage and that it subsequently results in the reduced number of OPCs.

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  • Histological detection of dynamic glial responses in the dysmyelinating Tabby-jimpy mutant brain 査読

    Masanao Ikeda, M. Ibrahim Hossain, Li Zhou, Masao Horie, Kazuhiro Ikenaka, Arata Horii, Hirohide Takebayashi

    Anatomical Science International   93 ( 1 )   119 - 127   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Tokyo  

    Oligodendrocytes (OLs) are glial cells that form myelin sheaths surrounding the axons in the central nervous system (CNS). Jimpy (jp) mutant mice are dysmyelinating disease models that show developmental abnormalities in myelinated OLs in the CNS. The causative gene in jp mice is the proteolipid protein (PLP) located on the X chromosome. Mutations in the jp allele result in exon 5 skipping and expression of abnormal PLP containing a C-terminal frame shift. Many lines of evidence suggest that abnormal PLP in OLs results in endoplasmic reticulum (ER) stress and cell death. To histologically detect glial responses in the jp mutant brain, we performed staining with lineage-specific markers. Using OL markers and OL progenitor cell marker staining, we identified reduced numbers of OL lineage cells in the jp mutant brain. Nuclear staining of the transcription factor Olig1 was observed in the Tabby-jp brain, whereas cytoplasmic Olig1 staining was observed in the wild-type brain at postnatal day 21, suggesting that active myelination was present in the mutant brain. Many microglial cells with activated morphology and intensive staining of CD11b microglia marker were observed in the internal capsule of the mutant brain, a region of white matter containing residual OLs. Activated astrocytes with high glial fibrillary acidic protein-immunoreactivity were also mainly observed in white matter. Finally, we performed in situ hybridization using C/EBP homologous protein (CHOP) antisense probes to detect ER stressed cells. CHOP mRNA was strongly expressed in residual OLs in the Tabby-jp mutant mice at postnatal stages. These data show that microglia and astrocytes exhibit dynamic glial activation in response to cell death of OLs during Tabby-jp pathogenesis, and that CHOP antisense probes may be a good marker for the detection of ER-stressed OLs in jp mutant mice.

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  • Author Correction: Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. 査読

    Morizawa YM, Hirayama Y, Ohno N, Shibata S, Shigetomi E, Sui Y, Nabekura J, Sato K, Okajima F, Takebayashi H, Okano H, Koizumi S

    Nature communications   8 ( 1 )   1598   2017年11月

  • Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway (vol 8, 28, 2017) 査読

    Yosuke M. Morizawa, Yuri Hirayama, Nobuhiko Ohno, Shinsuke Shibata, Eiji Shigetomi, Yang Sui, Junichi Nabekura, Koichi Sato, Fumikazu Okajima, Hirohide Takebayashi, Hideyuki Okano, Schuichi Koizumi

    NATURE COMMUNICATIONS   8 ( 1 )   28   2017年11月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    DOI: 10.1038/s41467-017-01594-1

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  • Motoneuron degeneration in the trigeminal motor nucleus innervating the masseter muscle in Dystonia musculorum mice. 査読

    Hossain MI, Horie M, Yoshioka N, Kurose M, Yamamura K, Takebayashi H

    Neurochemistry international   119   159 - 170   2017年10月

  • Hearing Loss Controlled by Optogenetic Stimulation of Nonexcitable Nonglial Cells in the Cochlea of the Inner Ear 査読

    Mitsuo P. Sato, Taiga Higuchi, Fumiaki Nin, Genki Ogata, Seishiro Sawamura, Takamasa Yoshida, Takeru Ota, Karin Hori, Shizuo Komune, Satoru Uetsuka, Samuel Choi, Masatsugu Masuda, Takahisa Watabe, Sho Kanzaki, Kaoru Ogawa, Hidenori Inohara, Shuichi Sakamoto, Hirohide Takebayashi, Katsumi Doi, Kenji F. Tanaka, Hiroshi Hibino

    FRONTIERS IN MOLECULAR NEUROSCIENCE   10   300   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FRONTIERS MEDIA SA  

    Light-gated ion channels and transporters have been applied to a broad array of excitable cells including neurons, cardiac myocytes, skeletal muscle cells and pancreatic b -cells in an organism to clarify their physiological and pathological roles. Nonetheless, among nonexcitable cells, only glial cells have been studied in vivo by this approach. Here, by optogenetic stimulation of a different nonexcitable cell type in the cochlea of the inner ear, we induce and control hearing loss. To our knowledge, deafness animal models using optogenetics have not yet been established. Analysis of transgenic mice expressing channelrhodopsin-2 (ChR2) induced by an oligodendrocyte-specific promoter identified this channel in nonglial cells-melanocytes-of an epithelial-like tissue in the cochlea. The membrane potential of these cells underlies a highly positive potential in a K C -rich extracellular solution, endolymph; this electrical property is essential for hearing. Illumination of the cochlea to activate ChR2 and depolarize the melanocytes significantly impaired hearing within a few minutes, accompanied by a reduction in the endolymphatic potential. After cessation of the illumination, the hearing thresholds and potential returned to baseline during several minutes. These responses were replicable multiple times. ChR2 was also expressed in cochlear glial cells surrounding the neuronal components, but slight neural activation caused by the optical stimulation was unlikely to be involved in the hearing impairment. The acuteonset, reversible and repeatable phenotype, which is inaccessible to conventional gene-targeting and pharmacological approaches, seems to at least partially resemble the symptom in a population of patients with sensorineural hearing loss. Taken together, this mouse line may not only broaden applications of optogenetics but also contribute to the progress of translational research on deafness.

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  • Epidermal growth factor singals attenuate phenotypic and functional development of neocortical GABA neurons 査読

    Hisaaki Namba, Tadasato Nagano, Eiichi Jodo, Satoshi Eifuku, Masao Horie, Hirohide Takebayashi, Yuriko Iwakura, Hidekazu Sotoyama, Nobuyuki Takei, Hiroyuki Nawa

    JOURNAL OF NEUROCHEMISTRY   142 ( 6 )   886 - 900   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Phenotypic development of neocortical GABA neurons is highly plastic and promoted by various neurotrophic factors such as neuregulin-1. A subpopulation of GABA neurons expresses not only neuregulin receptor (ErbB4) but also epidermal growth factor (EGF) receptor (ErbB1) during development, but the neurobiological action of EGF on this cell population is less understood than that of neuregulin-1. Here, we examined the effects of exogenous EGF on immature GABA neurons both in culture and in vivo and also explored physiological consequences in adults. We prepared low density cultures from the neocortex of rat embryos and treated neocortical neurons with EGF. EGF decreased protein levels of glutamic acid decar-boxylases (GAD65 and GAD67), and EGF influences on neuronal survival and glial proliferation were negligible or limited. The EGF treatment also diminished the frequency of miniature inhibitory postsynaptic currents (mIPSCs). In vivo administration of EGF to mouse pups reproduced the above GABAergic phenomena in neocortical culture. In EGF-injected postnatal mice, GAD- and parvalbumin-immunoreactivities were reduced in the frontal cortex. In addition, postnatal EGF treatment decreased mIPSC frequency in, and the density of, GABAergic terminals on pyramidal cells. Although these phenotypic influences on GABA neurons became less marked during development, it later resulted in the reduced beta- and gamma-powers of sound-evoked electroencephalogram in adults, which is regulated by parvalbumin-positive GABA neurons and implicated in the schizophrenia pathophysiology. These findings suggest that, in contrast to the ErbB4 ligand of neuregulin-1, the ErbB1 ligand of EGF exerts unique maturation-attenuating influences on developing cortical GABAergic neurons.

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  • BPAG1 in muscles: Structure and function in skeletal, cardiac and smooth muscle 査読

    Masao Horie, Nozomu Yoshioka, Hirohide Takebayashi

    SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY   69   26 - 33   2017年9月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

    BPAG1, also known as Dystonin or BP230, belongs to the plakin family of proteins, which has multiple cytoskeleton-binding domains. Several BPAG1 isoforms are produced by a single BPAG1 genomic locus using different promoters and exons. For example, BPAG1 a, BPAG1b, and BPAG1 e are predominantly expressed in the nervous system, muscle, and skin, respectively. Among BPAG1 isoforms, BPAG1 e is well studied because it was first identified as an autoantigen in patients with bullous pemphigoid, an autoimmune skin disease. BPAG1 e is a component of hemidesmosomes, the adhesion complexes that promote dermal-epidermal cohesion. In the nervous system, the role of BPAG1 a is also well studied because disruption of BPAG I a results in a phenotype identical to that of Dystonia musculorum (dt) mutants, which show progressive motor disorder. However, the expression and function of BPAG1 in muscles is not well studied. The aim of this review is to provide an overview of and highlight some recent findings on the expression and function of BPAG1 in muscles, which can assist future studies designed to delineate the role and regulation of BPAG1 in the dt mouse phenotype and in human hereditary sensory and autonomic neuropathy type 6 (HSAN6). (C) 2017 Elsevier Ltd. All rights reserved.

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  • An RNA-binding protein, Qki5, regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling 査読

    Yoshika Hayakawa-Yano, Satoshi Suyama, Masahiro Nogami, Masato Yugami, Ikuko Koya, Takako Furukawa, Li Zhou, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi, Atsushi Nakanishi, Hideyuki Okano, Masato Yano

    GENES & DEVELOPMENT   31 ( 18 )   1910 - 1925   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

    Cell type-specific transcriptomes are enabled by the action of multiple regulators, which are frequently expressed within restricted tissue regions. In the present study, we identify one such regulator, Quaking 5 (Qki5), as an RNA-binding protein (RNABP) that is expressed in early embryonic neural stem cells and subsequently down-regulated during neurogenesis. mRNA sequencing analysis in neural stem cell culture indicates that Qki proteins play supporting roles in the neural stem cell transcriptome and various forms of mRNA processing that may result from regionally restricted expression and subcellular localization. Also, our in utero electroporation gain-of-function study suggests that the nuclear-type Qki isoform Qki5 supports the neural stem cell state. We next performed in vivo transcriptome-wide protein-RNA interaction mapping to search for direct targets of Qki5 and elucidate how Qki5 regulates neural stem cell function. Combined with our transcriptome analysis, this mapping analysis yielded a bona fide map of Qki5-RNA interaction at single-nucleotide resolution, the identification of 892 Qki5 direct target genes, and an accurate Qki5-dependent alternative splicing rule in the developing brain. Last, our target gene list provides the first compelling evidence that Qki5 is associated with specific biological events; namely, cell-cell adhesion. This prediction was confirmed by histological analysis of mice in which Qki proteins were genetically ablated, which revealed disruption of the apical surface of the lateral wall in the developing brain. These data collectively indicate that Qki5 regulates communication between neural stem cells by mediating numerous RNA processing events and suggest new links between splicing regulation and neural stem cell states.

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  • A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells 査読

    Yuta Seki, Yuki Miyasaka, Sari Suzuki, Kenta Wada, Shumpei P. Yasuda, Kunie Matsuoka, Yasuhiro Ohshiba, Kentaro Endo, Rie Ishii, Hiroshi Shitara, Shin-ichiro Kitajiri, Naomi Nakagata, Hirohide Takebayashi, Yoshiaki Kikkawa

    PLOS ONE   12 ( 8 )   e0183477   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    An unconventional myosin encoded by the myosin VI gene (MYO6) contributes to hearing loss in humans. Homozygous mutations of MYO6 result in nonsyndromic profound congenital hearing loss, DFNB37. Kumamoto shaker/waltzer (ksv) mice harbor spontaneous mutations, and homozygous mutants exhibit congenital defects in balance and hearing caused by fusion of the stereocilia. We identified a Myo6(c.1381G>A) mutation that was found to be a p.E461K mutation leading to alternative splicing errors in Myo6 mRNA in ksv mutants. An analysis of the mRNA and protein expression in animals harboring this mutation suggested that most of the abnormal alternatively spliced isoforms of MYO6 are degraded in ksv mice. In the hair cells of ksv/ksv homozygotes, the MYO6 protein levels were significantly decreased in the cytoplasm, including in the cuticular plates. MYO6 and stereociliary taper-specific proteins were mislocalized along the entire length of the stereocilia of ksv/ksv mice, thus suggesting that MYO6 attached to taper-specific proteins at the stereociliary base. Histological analysis of the cochlear hair cells showed that the stereociliary fusion in the ksv/ksv mutants, developed through fusion between stereociliary bundles, raised cuticular plate membranes in the cochlear hair cells and resulted in incorporation of the bundles into the sheaths of the cuticular plates. Interestingly, the expression of the stereociliary rootlet-specific TRIO and F-actin binding protein (TRIOBP) was altered in ksv/ksv mice. The abnormal expression of TRIOBP suggested that the rootlets in the hair cells of ksv/ksv mice had excessive growth. Hence, these data indicated that decreased MYO6 levels in ksv/ksv mutants disrupt actin networks in the apical region of hair cells, thereby maintaining the normal structure of the cuticular plates and rootlets, and additionally provided a cellular basis for stereociliary fusion in Myo6 mutants.

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  • Oligodendrocyte precursor cells in the mouse optic nerve originate in the preoptic area 査読

    Katsuhiko Ono, Kengo Yoshii, Hiroyuki Tominaga, Hitoshi Gotoh, Tadashi Nomura, Hirohide Takebayashi, Kazuhiro Ikenaka

    BRAIN STRUCTURE & FUNCTION   222 ( 5 )   2441 - 2448   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER HEIDELBERG  

    The present study aims to examine the origin of oligodendrocyte progenitor cells (OPCs) in the mouse optic nerve (ON) by labeling OPCs in the fetal forebrain. The labeling of OPCs in the ON was performed by injection of a retrovirus vector carrying the lacZ gene into the lateral ventricle, or by inducible Cre/loxP of Olig2-positive cells. The retrovirus labeling revealed that ventricular zone-derived cells of the fetal forebrain relocated to the ON and differentiated into oligodendrocytes. In addition, lineage tracing of Olig2-positive cells and whole-mount staining of PDGFRa-positive cells demonstrated that OPCs appeared by E12.5 in the preoptic area, and spread caudally to enter the ON. Our results also suggest that OPCs generated during the early stage are depleted from the ON after maturation.

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  • Reconsidering Tonotopic Maps in the Auditory Cortex and Lemniscal Auditory Thalamus in Mice 査読

    Hiroaki Tsukano, Masao Horie, Shinpei Ohga, Kuniyuki Takahashi, Yamato Kubota, Ryuichi Hishida, Hirohide Takebayashi, Katsuei Shibuki

    FRONTIERS IN NEURAL CIRCUITS   11   14   2017年2月

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    記述言語:英語   出版者・発行元:FRONTIERS MEDIA SA  

    The auditory thalamus and auditory cortex (AC) are pivotal structures in the central auditory system. However, the thalamocortical mechanisms of processing sounds are largely unknown. Investigation of this process benefits greatly from the use of mice because the mouse is a powerful animal model in which various experimental techniques, especially genetic tools, can be applied. However, the use of mice has been limited in auditory research, and thus even basic anatomical knowledge of the mouse central auditory system has not been sufficiently collected. Recently, optical imaging combined with morphological analyses has enabled the elucidation of detailed anatomical properties of the mouse auditory system. These techniques have uncovered fine AC maps with multiple frequency-organized regions, each of which receives pointto- point thalamocortical projections from different origins inside the lemniscal auditory thalamus, the ventral division of the medial geniculate body (MGv). This precise anatomy now provides a platform for physiological research. In this mini review article, we summarize these recent achievements that will facilitate physiological investigations in the mouse auditory system.

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  • Independent tonotopy and thalamocortical projection patterns in two adjacent parts of the classical primary auditory cortex in mice 査読

    Hiroaki Tsukano, Masao Horie, Kuniyuki Takahashi, Ryuichi Hishida, Hirohide Takebayashi, Katsuei Shibuki

    NEUROSCIENCE LETTERS   637   26 - 30   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Amid recent amendment of delineation of a mouse auditory cortical map, a caudal auditory field, originally defined as the primary auditory cortex (AI), was divided into the AI and dorsomedial field (DM), based on distinct high frequency areas. A low frequency area was not previously established in the DM because responses to low frequency tones were weak in this area. This may lead to the misconception that the DM is an atypical region that lacks a low frequency band. In the current study, we confirmed that the DM has a low frequency area that is completely independent from the AI. First, we conducted flavoprotein fluorescence imaging with improved signal to noise ratio and revealed the presence of two separated low frequency areas in the AI and DM. Next, we injected a retrograde neural tracer along the tonotopic axis of the AI or DM to reveal the thalamic origins in the ventral division of the medial geniculate body (MGv). We found that neurons projecting to low frequency areas of the AI and DM occupied different locations within the MGv and mutually independent topographic organizations consisting of thalamic neurons projecting to the AI or DM. These results indicate that the AI and DM have distinct low frequency areas with distinct thalamic projections from the MGv. Our findings reaffirm that the AI and DM should be regarded as independent regions in the mouse auditory cortex. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.

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  • Characterization of novel dystonia musculorum mutant mice: Implications for central nervous system abnormality 査読

    Masao Horie, Kazuyuki Mekada, Hiromi Sano, Yoshiaki Kikkawa, Satomi Chiken, Takuro Someya, Keisuke Saito, M. Ibrahim Hossain, Masaaki Nameta, Kuniya Abe, Kenji Sakimura, Katsuhiko Ono, Atsushi Nambu, Atsushi Yoshiki, Hirohide Takebayashi

    NEUROBIOLOGY OF DISEASE   96   271 - 283   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (Dst(Gt)) mice. Compound heterozygotes showed a typical dt phenotype with sensory degeneration and progressive motor symptoms. DNA sequencing analysis identified a nonsense mutation within the spectrin repeats of the plakin domain. The novel mutant allele was named dt(23Rbrc). Motor abnormalities in homozygous dt(23Rbrc)/dt(23Rbrc) mice are not as severe as homozygous Dst(Gt)/Dst(Gt) mice. Histological analyses showed abnormal neurofilament (NF) accumulation in the nervous system of homozygous dt(23Rbrc)/dt(23Rbrc) mice, which is characteristic of the dt phenotype. We mapped the distribution of abnormal NF-accumulated neurons in the brain and found that they were located specifically in the brainstem, spinal cord, and in regions such as the vestibular nucleus, reticular nucleus, and red nucleus, which are implicated in posture and motor coordination pathways. The quantification of abnormal NF accumulation in the cytoplasm and spheroids (axons) of neurons showed that abnormal NF immunoreactivity was lower in homozygous dt(23Rbrc)/dt(23Rbrc) mice than in homozygous Dst(Gt)/Dst(Gt) mice. Therefore, we have identified a novel hypomorphic allele of dt, which causes histological abnormalities in the central nervous system that may account for the abnormal motor phenotype. This novel spontaneously occurring mutant may become a good model of hereditary sensory and autonomic neuropathy type 6, which is caused by mutations in the human DST gene. (C) 2016 Elsevier Inc. All rights reserved.

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  • Endoplasmic Reticulum-Localized Transmembrane Protein Dpy19L1 Is Required for Neurite Outgrowth 査読

    Keisuke Watanabe, Norihisa Bizen, Noboru Sato, Hirohide Takebayashi

    PLOS ONE   11 ( 12 )   e0167985   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The endoplasmic reticulum (ER), including the nuclear envelope, is a continuous and intricate membrane-bound organelle responsible for various cellular functions. In neurons, the ER network is found in cell bodies, axons, and dendrites. Recent studies indicate the involvement of the ER network in neuronal development, such as neuronal migration and axonal outgrowth. However, the regulation of neural development by ER-localized proteins is not fully understood. We previously reported that the multi-transmembrane protein Dpy19L1 is required for neuronal migration in the developing mouse cerebral cortex. A Dpy19L family member, Dpy19L2, which is a causative gene for human Globozoospermia, is suggested to act as an anchor of the acrosome to the nuclear envelope. In this study, we found that the patterns of exogenous Dpy19L1 were partially coincident with the ER, including the nuclear envelope in COS-7 cells at the level of the light microscope. The reticular distribution of Dpy19L1 was disrupted by microtubule depolymerization that induces retraction of the ER. Furthermore, Dpy19L1 showed a similar distribution pattern with a ER marker protein in embryonic mouse cortical neurons. Finally, we showed that Dpy19L1 knockdown mediated by siRNA resulted in decreased neurite outgrowth in cultured neurons. These results indicate that transmembrane protein Dpy19L1 is localized to the ER membrane and regulates neurite extension during development.

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  • Characteristic Microglial Features in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids 査読

    Mari Tada, Takuya Konno, Masayoshi Tada, Toshiyuki Tezuka, Takeshi Miura, Naomi Mezaki, Ken-ichi Okazaki, Musashi Arakawa, Kyoko Itoh, Toru Yamamoto, Hideaki Yokoo, Nobuaki Yoshikura, Kenji Ishihara, Masao Horie, Hirohide Takebayashi, Yasuko Toyoshima, Makoto Naito, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi, Takeshi Ikeuchi, Akiyoshi Kakita

    ANNALS OF NEUROLOGY   80 ( 4 )   554 - 565   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Objective: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R).
    Methods: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed.
    Results: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow.
    Interpretation: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations.

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  • Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy. 査読

    Muona M, Ishimura R, Laari A, Ichimura Y, Linnankivi T, Keski-Filppula R, Herva R, Rantala H, Paetau A, Pöyhönen M, Obata M, Uemura T, Karhu T, Bizen N, Takebayashi H, McKee S, Parker MJ, Akawi N, McRae J, Hurles ME, DDD Study, Kuismin O, Kurki MI, Anttonen AK, Tanaka K, Palotie A, Waguri S, Lehesjoki AE, Komatsu M

    American journal of human genetics   99 ( 3 )   683 - 694   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • The Dorsoventral Boundary of the Germinal Zone is a Specialized Niche for the Generation of Cortical Oligodendrocytes during a Restricted Temporal Window 査読

    Masae Naruse, Yugo Ishino, Akhilesh Kumar, Katsuhiko Ono, Hirohide Takebayashi, Masahiro Yamaguchi, Yasuki Ishizaki, Kazuhiro Ikenaka, Seiji Hitoshi

    CEREBRAL CORTEX   26 ( 6 )   2800 - 2810   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS INC  

    Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature to become oligodendrocytes (OLs), and form myelin in the postnatal brain. Recently, it has been proposed that early-born OPCs derived from the ventral forebrain are eradicated postnatally and that late-born OLs predominate in the cortex of the adult mouse brain. However, intrinsic and extrinsic factors that specify the ability of self-renewing multipotent neural stem cells in the embryonic brain to generate cortical OL-lineage cells remain largely unknown. Using an inducible Cre/loxP system to permanently label Nestin- and Olig2-lineage cells, we identified that cortical OL-lineage cells start differentiating from neural stem cells within a restricted temporal window just prior to E16.5 through P10. We then showed, by means of electroporation of a Cre expression plasmid into the VZ/SVZ of E15.5 reporter mouse brains, that neural precursor cells in the dorsal VZ/SVZ are inhibited by Wnt signaling from contributing to cortical OLs in the adult brain. In contrast, neural precursor cells present in the dorsoventral boundary VZ/SVZ produce a significant amount of OLs in the adult cortex. Our results suggest that neural stem cells at this boundary are uniquely specialized to produce myelin-forming OLs in the cortex.

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  • Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes 査読

    Ryoko Takeuchi, Mari Tada, Atsushi Shiga, Yasuko Toyoshima, Takuya Konno, Tomoe Sato, Hiroaki Nozaki, Taisuke Kato, Masao Horie, Hiroshi Shimizu, Hirohide Takebayashi, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   4 ( 1 )   61   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.

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  • Quantitative map of multiple auditory cortical regions with a stereotaxic fine-scale atlas of the mouse brain 査読

    Hiroaki Tsukano, Masao Horie, Ryuichi Hishida, Kuniyuki Takahashi, Hirohide Takebayashi, Katsuei Shibuki

    SCIENTIFIC REPORTS   6   22315   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Optical imaging studies have recently revealed the presence of multiple auditory cortical regions in the mouse brain. We have previously demonstrated, using flavoprotein fluorescence imaging, at least six regions in the mouse auditory cortex, including the anterior auditory field (AAF), primary auditory cortex (AI), the secondary auditory field (AII), dorsoanterior field (DA), dorsomedial field (DM), and dorsoposterior field (DP). While multiple regions in the visual cortex and somatosensory cortex have been annotated and consolidated in recent brain atlases, the multiple auditory cortical regions have not yet been presented from a coronal view. In the current study, we obtained regional coordinates of the six auditory cortical regions of the C57BL/6 mouse brain and illustrated these regions on template coronal brain slices. These results should reinforce the existing mouse brain atlases and support future studies in the auditory cortex.

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  • Spatiotemporal regulation of neural progenitor identities by transcription factors 査読

    Mikio Hoshino, Yusuke Seto, Tomoya Nakatani, Yoshiya Kawaguchi, Kazuhiro Ikenaka, Hirohide Takebayashi, Yuichi Ono, Mayumi Yamada

    INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE   47   70 - 71   2015年12月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

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  • Draxin from neocortical neurons controls the guidance of thalamocortical projections into the neocortex 査読

    Yohei Shinmyo, M. Asrafuzzaman Riyadh, Giasuddin Ahmed, Iftekhar Bin Naser, Mahmud Hossain, Hirohide Takebayashi, Hiroshi Kawasaki, Kunimasa Ohta, Hideaki Tanaka

    NATURE COMMUNICATIONS   6   10232   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    The thalamocortical tract carries sensory information to the neocortex. It has long been recognized that the neocortical pioneer axons of subplate neurons are essential for thalamocortical development. Herein we report that an axon guidance cue, draxin, is expressed in early-born neocortical neurons, including subplate neurons, and is necessary for thalamocortical development. In draxin (-/-) mice, thalamocortical axons do not enter the neocortex. This phenotype is sufficiently rescued by the transgenic expression of draxin in neocortical neurons. Genetic interaction data suggest that draxin acts through Deleted in colorectal cancer (DCC) and Neogenin (Neo1), to regulate thalamocortical projections in vivo. Draxin promotes the outgrowth of thalamic axons in vitro and this effect is abolished in thalamic neurons from Dcc and Neo1 double mutants. These results suggest that draxin from neocortical neurons controls thalamocortical projections into the neocortex, and that this effect is mediated through the DCC and Neo1 receptors.

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  • Oligodendrogenesis in the fornix of adult mouse brain; the effect of LPS-induced inflammatory stimulation 査読

    Shohei Fukushima, Kazunori Nishikawa, Eriko Furube, Shiori Muneoka, Katsuhiko Ono, Hirohide Takebayashi, Seiji Miyata

    BRAIN RESEARCH   1627   52 - 69   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Evidence have been accumulated that continuous oligodendrogenesis occurs in the adult mammalian brain. The fornix, projection and commissure pathway of hippocampal neurons, carries signals from the hippocampus to other parts of the brain and has critical role in memory and learning. However, basic characterization of adult oligodendrogenesis in this brain region is not well understood. In the present study, therefore, we aimed to examine the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) and the effect of acute inflammatory stimulation on oligodendrogenesis in the fornix of adult mouse. We demonstrated the proliferation of OPCs and a new generation of mature oligodendrocytes by using bromodeoxyuridine and Ki67 immunohistochemistry. Oligodendrogenesis of adult fornix was also demonstrated by using oligodendrocyte transcription factor 2 transgenic mouse. A single systemic administration of lipopolysaccharide (LPS) attenuated proliferation of OPCs in the fornix together with reduced proliferation of hippocampal neural stem/progenitor cells. Time course analysis showed that a single administration of LPS attenuated the proliferation of OPCs during 24-48 h. On the other hand, consecutive administration of LPS did not suppress proliferation of OPCs. The treatment of LPS did not affect differentiation of OPCs into mature oligodendrocytes. Treatment of a microglia inhibitor minocycline significantly attenuated basal proliferation of OPCs under normal condition. In conclusion, the present study indicates that continuous oligodendrogenesis occurs and a single administration of LPS transiently attenuates proliferation of OPCs without changing differentiation in the fornix of the adult mouse brains. (C) 2015 Elsevier B.V. All rights reserved.

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  • Specific distribution of non-phosphorylated neurofilaments characterizing each subfield in the mouse auditory cortex 査読

    Masao Horie, Hiroaki Tsukano, Hirohide Takebayashi, Katsuei Shibuki

    NEUROSCIENCE LETTERS   606   182 - 187   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Recent imaging studies revealed the presence of Binctional subfields in the mouse auditory cortex. However, little is known regarding the morphological basis underlying the functional differentiation. Distribution of particular molecules is the key information that may be applicable for identifying auditory subfields in the post-mortem brain. Immunoreactive patterns using SMI-32 monoclonal antibody against non-phosphorylated neurofilament (NNF) have already been used to identify or parcellate various brain regions in various animals. In the present study, we investigated whether distribution of NNF is a reliable marker for identifying functional subfields in the mouse auditory cortex, and found that each auditory subfield has region-specific cellular and laminar patterns of immunoreactivity for NNF. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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  • Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb 査読

    Mitsuko Nakashima, Hirotomo Saitsu, Nobuyuki Takei, Jun Tohyama, Mitsuhiro Kato, Hiroki Kitaura, Masaaki Shiina, Hiroshi Shirozu, Hiroshi Masuda, Keisuke Watanabe, Chihiro Ohba, Yoshinori Tsurusaki, Noriko Miyake, Yingjun Zheng, Tatsuhiro Sato, Hirohide Takebayashi, Kazuhiro Ogata, Shigeki Kameyama, Akiyoshi Kakita, Naomichi Matsumoto

    Annals of Neurology   78 ( 3 )   375 - 386   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:John Wiley and Sons Inc.  

    Objective: Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb. Methods: We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments. Results: We identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. Interpretation: We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb.

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  • Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb 査読

    Mitsuko Nakashima, Hirotomo Saitsu, Nobuyuki Takei, Jun Tohyama, Mitsuhiro Kato, Hiroki Kitaura, Masaaki Shiina, Hiroshi Shirozu, Hiroshi Masuda, Keisuke Watanabe, Chihiro Ohba, Yoshinori Tsurusaki, Noriko Miyake, Yingjun Zheng, Tatsuhiro Sato, Hirohide Takebayashi, Kazuhiro Ogata, Shigeki Kameyama, Akiyoshi Kakita, Naomichi Matsumoto

    Annals of Neurology   78 ( 3 )   375 - 386   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:John Wiley and Sons Inc.  

    Objective: Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb. Methods: We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments. Results: We identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. Interpretation: We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb.

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  • Oligodendrocyte generation during mouse development 査読

    Hirohide Takebayashi, Kazuhiro Ikenaka

    GLIA   63 ( 8 )   1350 - 1356   2015年8月

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    記述言語:英語   出版者・発行元:WILEY  

    Oligodendrocytes (OLs) are glial cells, which generate myelin in the central nervous system. Their interesting developmental features attract many neurobiologists eager to study cell differentiation, gene expression regulation, or dynamic morphogenesis. Their primary role in protecting the axons has major impacts in the medical research field: in multiple sclerosis, a demyelinating disease in which remyelination is blocked. Oligodendrogenesis is involved in higher brain function including motor skill learning and cognitive function. Here, we review advances in the research on OL development and highlight areas where questions remain to be answered in both developmental biology and neurobiology related aspects. GLIA 2015;63:1350-1356

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  • Impaired clustered protocadherin-α leads to aggregated retinogeniculate terminals and impaired visual acuity in mice. 査読

    Meguro R, Hishida R, Tsukano H, Yoshitake K, Imamura R, Tohmi M, Kitsukawa T, Hirabayashi T, Yagi T, Takebayashi H, Shibuki K

    Journal of neurochemistry   133 ( 1 )   66 - 72   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Delineation of a frequency-organized region isolated from the mouse primary auditory cortex 査読

    Hiroaki Tsukano, Masao Horie, Takeshi Bo, Arikuni Uchimura, Ryuichi Hishida, Masaharu Kudoh, Kuniyuki Takahashi, Hirohide Takebayashi, Katsuei Shibuki

    JOURNAL OF NEUROPHYSIOLOGY   113 ( 7 )   2900 - 2920   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    The primary auditory cortex (AI) is the representative recipient of information from the ears in the mammalian cortex. However, the delineation of the AI is still controversial in a mouse. Recently, it was reported, using optical imaging, that two distinct areas of the AI, located ventrally and dorsally, are activated by high-frequency tones, whereas only one area is activated by low-frequency tones. Here, we show that the dorsal high-frequency area is an independent region that is separated from the rest of the AI. We could visualize the two distinct high-frequency areas using flavoprotein fluorescence imaging, as reported previously. SMI-32 immunolabeling revealed that the dorsal region had a different cytoarchitectural pattern from the rest of the AI. Specifically, the ratio of SMI-32-positive pyramidal neurons to nonpyramidal neurons was larger in the dorsal high-frequency area than the rest of the AI. We named this new region the dorsomedial field (DM). Retrograde tracing showed that neurons projecting to the DM were localized in the rostral part of the ventral division of the medial geniculate body with a distinct frequency organization, where few neurons projected to the AI. Furthermore, the responses of the DM to ultrasonic courtship songs presented by males were significantly greater in females than in males; in contrast, there was no sex difference in response to artificial pure tones. Our findings offer a basic outline on the processing of ultrasonic vocal information on the basis of the precisely subdivided, multiple frequency-organized auditory cortex map in mice.

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  • Expression of the Olig gene family in the developing mouse inner ear 査読

    Eriko Kanaya, Kohei Yamahara, Takayuki Okano, Atsuhiro Yoshida, Tatsuya Katsuno, Hirohide Takebayashi, Juichi Ito, Norio Yamamoto

    GENE EXPRESSION PATTERNS   17 ( 2 )   79 - 86   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Transcription factors are believed to play key roles in determining cell fate in inner ear development. Olig genes, which are basic helix-loop-helix transcription factors, have been reported to play important roles in the development of the central nervous system. However, members of this family have not previously been implicated in inner ear development, despite the similarity between otocyst and neural tube development. Olig1 begins to be expressed at the ventral domain of the otocyst at embryonic day (E) 9.5, and Olig1 expression in the epithelium of the developing inner ear persists to El 5.5. Olig2 expression is localized to the cochleovestibular ganglia from E12.5 through E14.5. Olig3 has a diffuse expression pattern in the developing inner ear from E12.5 through the postnatal stage. Furthermore, at early stages of inner ear development, the Olig1 expression domain overlaps a region that is positive for Sox2 and Jagged1. This observation indicates that Olig1 may play an important role in the specification of the prosensory domain in the developing inner ear. As Olig genes are expressed in the mouse developing inner ear in a temporospatially distinct fashion, they may play substantial roles in the regulation of mammalian inner ear development. (C) 2015 Elsevier B.V. All rights reserved.

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  • Disruption of actin-binding domain-containing Dystonin protein causes dystonia musculorum in mice 査読

    Masao Horie, Keisuke Watanabe, Asim K. Bepari, Jun-ichiro Nashimoto, Kimi Araki, Hiromi Sano, Satomi Chiken, Atsushi Nambu, Katsuhiko Ono, Kazuhiro Ikenaka, Akiyoshi Kakita, Ken-ichi Yamamura, Hirohide Takebayashi

    EUROPEAN JOURNAL OF NEUROSCIENCE   40 ( 10 )   3458 - 3471   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst(Gt)) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl--D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst(Gt) mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst(Gt) allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.

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  • Olig3 Is Not Involved in the Ventral Patterning of Spinal Cord 査読

    Zijing Liu, Xuemei Hu, Chengcheng Huang, Kang Zheng, Hirohide Takebayashi, Cheng Cao, Mengsheng Qiu

    PLOS ONE   9 ( 10 )   e111076   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    At embryonic stages, Olig3 is initially expressed in the dorsal-most region of the spinal cord, but later in the ventral marginal zone as well. Previous studies indicated that Olig3 controlled the patterning of dorsal spinal cord and loss of Olig3 function led to the re-specification of dI2 and dI3 neurons into dI4 interneurons. However, the role of Olig3 in regulating the development of ventral spinal cord has remained unknown. BrdU labeling demonstrated that ventral Olig3 was expressed in the post-mitotic neurons and Olig3+ cells seen at late embryonic stages were born at the earlier stage but remained in the marginal zone throughout embryogenesis. Loss-of-function and gain-of-function experiment indicated that Nkx2.2 regulated the expression of Olig3 in V3 interneurons. However, Olig3 mutation didn't apparently affect the generation and migration of ventral neurons. These findings suggest that Olig3 plays different roles in regulating the development of dorsal and ventral spinal cord.

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  • Development of the prethalamus is crucial for thalamocortical projection formation and is regulated by Olig2 査読

    Katsuhiko Ono, Adrien Clavairoly, Tadashi Nomura, Hitoshi Gotoh, Aoi Uno, Olivier Armant, Hirohide Takebayashi, Qi Zhang, Kenji Shimamura, Shigeyoshi Itohara, Carlos M. Parras, Kazuhiro Ikenaka

    DEVELOPMENT   141 ( 10 )   2075 - 2084   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COMPANY OF BIOLOGISTS LTD  

    Thalamocortical axons (TCAs) pass through the prethalamus in the first step of their neural circuit formation. Although it has been supposed that the prethalamus is an intermediate target for thalamocortical projection formation, much less is known about the molecular mechanisms of this targeting. Here, we demonstrated the functional implications of the prethalamus in the formation of this neural circuit. We show that Olig2 transcription factor, which is expressed in the ventricular zone (VZ) of prosomere 3, regulates prethalamus formation, and loss of Olig2 results in reduced prethalamus size in early development, which is accompanied by expansion of the thalamic eminence (TE). Extension of TCAs is disorganized in the Olig2-KO dorsal thalamus, and initial elongation of TCAs is retarded in the Olig2-KO forebrain. Microarray analysis demonstrated upregulation of several axon guidance molecules, including Epha3 and Epha5, in the Olig2-KO basal forebrain. In situ hybridization showed that the prethalamus in the wild type excluded the expression of Epha3 and Epha5, whereas loss of Olig2 resulted in reduction of this Ephas-negative area and the corresponding expansion of the Ephas-positive TE. Dissociated cultures of thalamic progenitor cells demonstrated that substrate-bound EphA3 suppresses neurite extension from dorsal thalamic neurons. These results indicate that Olig2 is involved in correct formation of the prethalamus, which leads to exclusion of the EphA3-expressing region and is crucial for proper TCA formation. Our observation is the first report showing the molecular mechanisms underlying how the prethalamus acts on initial thalamocortical projection formation.

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  • Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum 査読

    Yusuke Seto, Tomoya Nakatani, Norihisa Masuyama, Shinichiro Taya, Minoru Kumai, Yasuko Minaki, Akiko Hamaguchi, Yukiko U. Inoue, Takayoshi Inoue, Satoshi Miyashita, Tomoyuki Fujiyama, Mayumi Yamada, Heather Chapman, Kenneth Campbell, Mark A. Magnuson, Christopher V. Wright, Yoshiya Kawaguchi, Kazuhiro Ikenaka, Hirohide Takebayashi, Shin'ichi Ishiwata, Yuichi Ono, Mikio Hoshino

    NATURE COMMUNICATIONS   5   3337   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    In the cerebellum, all GABAergic neurons are generated from the Ptf1a-expressing ventricular zone (Ptf1a domain). However, the machinery to produce different types of GABAergic neurons remains elusive. Here we show temporal regulation of distinct GABAergic neuron progenitors in the cerebellum. Within the Ptf1a domain at early stages, we find two subpopulations; dorsally and ventrally located progenitors that express Olig2 and Gsx1, respectively. Lineage tracing reveals the former are exclusively Purkinje cell progenitors (PCPs) and the latter Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. In gain-and loss-of-function mutants for Gsx1 and Olig1/2, we observe abnormal transitioning from PCPs to PIPs at inappropriate developmental stages. Our findings suggest that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, and contributes to understanding temporal control of neuronal progenitor identities.

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  • Age-related deterioration of cortical responses to slow FM sounds in the auditory belt region of adult C57BL/6 mice 査読

    Hiroaki Tsukano, Masao Horie, Yuusuke Honma, Shinpei Ohga, Ryuichi Hishida, Hirohide Takebayashi, Sugata Takahashi, Katsuei Shibuki

    NEUROSCIENCE LETTERS   556   204 - 209   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    To compare age-related deterioration of neural responses in each subfield of the auditory cortex in C57BL/6 mice, we evaluated amplitudes of tonal responses in young (5-11 weeks old) and adult (16-23 weeks old) groups using transcranial flavoprotein fluorescence imaging. Cortical responses to 20-kHz amplitude-modulated (AM) sounds, which were mainly found in the anterior auditory field (AAF) and the primary auditory cortex (AI) of the core region, were not markedly different between the two groups. In contrast, cortical responses to direction reversal of slow frequency-modulated (FM) sounds, which were mainly found in the ultrasonic field (UF), were significantly disrupted in the adult group compared with those in the young group. To investigate the mechanisms underlying such age-related deterioration, biotinylated dextran amine (BDA) was injected into UF. The number of retrograde labeled neurons in the dorsal division of the medial geniculate body (MGd) was markedly reduced in the adult group compared with that in the young group. These results strongly suggest that cortical responses to FM direction reversal in UF of adult C57BL/6 mice are mainly deteriorated by loss of non-lemniscal thalamic inputs from MGd to UF due to aging. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • Dual compartments of the ventral division of the medial geniculate body projecting to the core region of the auditory cortex in C57BL/6 mice. 査読

    Horie Masao, Tsukano Hiroaki, Hishida Ryuichi, Takebayashi Hirohide, Shibuki Katsuei

    Neurosci Res   76 ( 4 )   207 - 212   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We investigated precise projection patterns from the ventral division of the medial geniculate body (MGv) projecting to the core region of the auditory cortex in C57BL/6 mice. The core region in mice comprises two different tonotopically organized areas, the anterior auditory field (AAF) and the primary auditory cortex (AI). In the present study, AAF and AI were functionally identified using flavoprotein fluorescence imaging. Biotinylated dextran amine (BDA) was injected iontophoretically into the tonotopic bands to 5kHz and 20kHz in AAF, and those to 5kHz, 10kHz, and 20kHz in AI for staining MGv neurons projecting to the injected sites. MGv neurons projecting to AAF were found in the medial part of MGv, while MGv neurons projecting to AI were found in the lateral part. In the medial part of MGv, areas projecting to 5-20kHz bands in AAF were aligned along the medio lateral axis. In the lateral part of MGv, areas projecting to 5-20kHz bands in AI were aligned along the dorso ventral axis. These results indicate that AAF and AI receive auditory information via two different MGv compartments with independent tonotopic axes, respectively.

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  • Olig2-lineage cells preferentially differentiate into oligodendrocytes but their processes degenerate at the chronic demyelinating stage of proteolipid protein-overexpressing mouse 査読

    Takahiro Shimizu, Kenji F. Tanaka, Hirohide Takebayashi, Mikito Higashi, Wilaiwan Wisesmith, Katsuhiko Ono, Seiji Hitoshi, Kazuhiro Ikenaka

    Journal of Neuroscience Research   91 ( 2 )   178 - 186   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:2  

    In chronic demyelinating lesions of the central nervous system, insufficient generation of oligodendrocytes (OLs) is not due to a lack of oligodendrocyte precursor cells (OPCs), because the accumulation of OPCs and premyelinating OLs can be observed within these lesions. Here we sought to identify the basis for the failure of OLs to achieve terminal differentiation in chronic demyelinating lesions through the utilization of plp1-overexpressing (Plp tg/-) mice. These mice are characterized by progressive demyelination in young adults and chronic demyelinating lesions at more mature stages. We show that neural stem cells, which are the precursors of OL-lineage cells, are present in the Plp tg/- mouse brain and that their multipotentiality and ability to self-renew are comparable to those of wild-type adults in culture. Lineage-tracing experiments using a transgenic mouse line, in which an inducible Cre recombinase is knocked in at the Olig2 locus, revealed that Olig2-lineage cells preferentially differentiated into OPCs and premyelinating OLs, but not into astrocytes, in the Plp tg/- mouse brain. These Olig2-lineage cells matured to express myelin basic protein but after that their processes degenerated in the chronic demyelinating lesions of the Plp tg/- brain. These results indicate that in chronic demyelinated lesions more OL-lineage cells are produced as part of the repair process, but their processes degenerate after maturation. © 2012 Wiley Periodicals, Inc.

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  • Identification of Optogenetically Activated Striatal Medium Spiny Neurons by Npas4 Expression 査読

    Asim K. Bepari, Hiromi Sano, Nobuaki Tamamaki, Atsushi Nambu, Kenji F. Tanaka, Hirohide Takebayashi

    PLOS ONE   7 ( 12 )   e52783   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Optogenetics is a powerful neuromodulatory tool with many unique advantages to explore functions of neuronal circuits in physiology and diseases. Yet, interpretation of cellular and behavioral responses following in vivo optogenetic manipulation of brain activities in experimental animals often necessitates identification of photoactivated neurons with high spatial resolution. Although tracing expression of immediate early genes (IEGs) provides a convenient approach, neuronal activation is not always followed by specific induction of widely used neuronal activity markers like c-fos, Egr1 and Arc. In this study we performed unilateral optogenetic stimulation of the striatum in freely moving transgenic mice that expressed a channelrhodopsin-2 (ChR2) variant ChR2(C128S) in striatal medium spiny neurons (MSNs). We found that in vivo blue light stimulation significantly altered electrophysiological activity of striatal neurons and animal behaviors. To identify photoactivated neurons we then analyzed IEG expression patterns using in situ hybridization. Upon light illumination an induction of c-fos was not apparent whereas another neuronal IEG Npas4 was robustly induced in MSNs ipsilaterally. Our results demonstrate that tracing Npas4 mRNA expression following in vivo optogenetic modulation can be an effective tool for reliable and sensitive identification of activated MSNs in the mouse striatum.

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  • Nkx2.2+Progenitors Generate Somatic Motoneurons in the Chick Spinal Cord 査読

    Hitoshi Gotoh, Katsuhiko Ono, Tadashi Nomura, Hirohide Takebayashi, Hidekiyo Harada, Harukazu Nakamura, Kazuhiro Ikenaka

    PLOS ONE   7 ( 12 )   e51581   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Heterogeneous classes of neurons are present in the spinal cord and are essential for its function. Expression patterns of transcription factors in neural progenitor cells determine neuron subtypes during development. Nkx2.2 is expressed in the progenitor cell pool located just ventrally to the Olig2-positive pool and is indispensable for V3 interneuron generation in the spinal cord and also for visceral motoneuron generation in the hindbrain. However, whether Nkx2.2-positive progenitor cells generate diverse classes of neuron is not fully understood. Using a chick lineage tracing method in a genetically-defined manner, we found that Nkx2.2-expressing progenitor cells differentiate into general visceral motoneurons as well as sim1-positive V3 interneurons. Surprisingly, we further observed that Nkx2.2-expressing progenitors differentiate into somatic motoneuron. Our findings suggest that the different classes of motoneurons are derived from more complex sources than were previously expected in the chick spinal cord.

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  • Visualization of odor-induced neuronal activity by immediate early gene expression 査読

    Asim K. Bepari, Keisuke Watanabe, Masahiro Yamaguchi, Nobuaki Tamamaki, Hirohide Takebayashi

    BMC NEUROSCIENCE   13   140   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Sensitive detection of sensory-evoked neuronal activation is a key to mechanistic understanding of brain functions. Since immediate early genes (IEGs) are readily induced in the brain by environmental changes, tracing IEG expression provides a convenient tool to identify brain activity. In this study we used in situ hybridization to detect odor-evoked induction of ten IEGs in the mouse olfactory system. We then analyzed IEG induction in the cyclic nucleotide-gated channel subunit A2 (Cnga2)-null mice to visualize residual neuronal activity following odorant exposure since CNGA2 is a key component of the olfactory signal transduction pathway in the main olfactory system.
    Results: We observed rapid induction of as many as ten IEGs in the mouse olfactory bulb (OB) after olfactory stimulation by a non-biological odorant amyl acetate. A robust increase in expression of several IEGs like c-fos and Egr1 was evident in the glomerular layer, the mitral/tufted cell layer and the granule cell layer. Additionally, the neuronal IEG Npas4 showed steep induction from a very low basal expression level predominantly in the granule cell layer. In Cnga2-null mice, which are usually anosmic and sexually unresponsive, glomerular activation was insignificant in response to either ambient odorants or female stimuli. However, a subtle induction of c-fos took place in the OB of a few Cnga2-mutants which exhibited sexual arousal. Interestingly, very strong glomerular activation was observed in the OB of Cnga2-null male mice after stimulation with either the neutral odor amyl acetate or the predator odor 2, 3, 5-trimethyl-3-thiazoline (TMT).
    Conclusions: This study shows for the first time that in vivo olfactory stimulation can robustly induce the neuronal IEG Npas4 in the mouse OB and confirms the odor-evoked induction of a number of IEGs. As shown in previous studies, our results indicate that a CNGA2-independent signaling pathway(s) may activate the olfactory circuit in Cnga2-null mice and that neuronal activation which correlates to behavioral difference in individual mice is detectable by in situ hybridization of IEGs. Thus, the in situ hybridization probe set we established for IEG tracing can be very useful to visualize neuronal activity at the cellular level.

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  • Subventricular Zone-Derived Oligodendrogenesis in Injured Neonatal White Matter in Mice Enhanced by a Nonerythropoietic Erythropoietin Derivative 査読

    Eisuke Kako, Naoko Kaneko, Mineyoshi Aoyama, Hideki Hida, Hirohide Takebayashi, Kazuhiro Ikenaka, Kiyofumi Asai, Hajime Togari, Kazuya Sobue, Kazunobu Sawamoto

    STEM CELLS   30 ( 10 )   2234 - 2247   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Perinatal hypoxia-ischemia (HI) frequently causes white-matter injury, leading to severe neurological deficits and mortality, and only limited therapeutic options exist. The white matter of animal models and human patients with HI-induced brain injury contains increased numbers of oligodendrocyte progenitor cells (OPCs). However, the origin and fates of these OPCs and their potential to repair injured white matter remain unclear. Here, using cell-type- and region-specific genetic labeling methods in a mouse HI model, we characterized the Olig2-expressing OPCs. We found that after HI, Olig2+ cells increased in the posterior part of the subventricular zone (pSVZ) and migrated into the injured white matter. However, their oligodendrocytic differentiation efficiency was severely compromised compared with the OPCs in normal tissue, indicating the need for an intervention to promote their differentiation. Erythropoietin (EPO) treatment is a promising candidate, but it has detrimental effects that preclude its clinical use for brain injury. We found that long-term postinjury treatment with a nonerythropoietic derivative of EPO, asialo-erythropoietin, promoted the maturation of pSVZ-derived OPCs and the recovery of neurological function, without affecting hematopoiesis. These results demonstrate the limitation and potential of endogenous OPCs in the pSVZ as a therapeutic target for treating neonatal white-matter injury. STEM Cells2012;30:22342247

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  • Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche 査読

    Daniel A. Lee, Joseph L. Bedont, Thomas Pak, Hong Wang, Juan Song, Ana Miranda-Angulo, Vani Takiar, Vanessa Charubhumi, Francesca Balordi, Hirohide Takebayashi, Susan Aja, Eric Ford, Gordon Fishell, Seth Blackshaw

    NATURE NEUROSCIENCE   15 ( 5 )   700 - 702   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism.

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  • Role of motoneuron-derived neurotrophin 3 in survival and axonal projection of sensory neurons during neural circuit formation 査読

    Noriyoshi Usui, Keisuke Watanabe, Katsuhiko Ono, Koichi Tomita, Nobuaki Tamamaki, Kazuhiro Ikenaka, Hirohide Takebayashi

    DEVELOPMENT   139 ( 6 )   1125 - 1132   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COMPANY OF BIOLOGISTS LTD  

    Sensory neurons possess the central and peripheral branches and they form unique spinal neural circuits with motoneurons during development. Peripheral branches of sensory axons fasciculate with the motor axons that extend toward the peripheral muscles from the central nervous system (CNS), whereas the central branches of proprioceptive sensory neurons directly innervate motoneurons. Although anatomically well documented, the molecular mechanism underlying sensory-motor interaction during neural circuit formation is not fully understood. To investigate the role of motoneuron on sensory neuron development, we analyzed sensory neuron phenotypes in the dorsal root ganglia (DRG) of Olig2 knockout (KO) mouse embryos, which lack motoneurons. We found an increased number of apoptotic cells in the DRG of Olig2 KO embryos at embryonic day (E) 10.5. Furthermore, abnormal axonal projections of sensory neurons were observed in both the peripheral branches at E10.5 and central branches at E15.5. To understand the motoneuron-derived factor that regulates sensory neuron development, we focused on neurotrophin 3 (Ntf3; NT-3), because Ntf3 and its receptors (Trk) are strongly expressed in motoneurons and sensory neurons, respectively. The significance of motoneuron-derived Ntf3 was analyzed using Ntf3 conditional knockout (cKO) embryos, in which we observed increased apoptosis and abnormal projection of the central branch innervating motoneuron, the phenotypes being apparently comparable with that of Olig2 KO embryos. Taken together, we show that the motoneuron is a functional source of Ntf3 and motoneuron-derived Ntf3 is an essential pre-target neurotrophin for survival and axonal projection of sensory neurons.

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  • A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors 査読

    Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Keisuke Watanabe, Hirohide Takebayashi, Hiroshi Kiyonari, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya

    NATURE NEUROSCIENCE   15 ( 3 )   373 - U193   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho-regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho-associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration.

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  • Dpy19l1, a multi-transmembrane protein, regulates the radial migration of glutamatergic neurons in the developing cerebral cortex 査読

    Keisuke Watanabe, Hirohide Takebayashi, Asim K. Bepari, Shigeyuki Esumi, Yuchio Yanagawa, Nobuaki Tamamaki

    DEVELOPMENT   138 ( 22 )   4979 - 4990   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COMPANY OF BIOLOGISTS LTD  

    During corticogenesis, the regulation of neuronal migration is crucial for the functional organization of the neocortex. Glutamatergic neurons are major excitatory components of the mammalian neocortex. In order to elucidate the specific molecular mechanisms underlying their development, we used single-cell microarray analysis to screen for mouse genes that are highly expressed in developing glutamatergic neurons. We identified dpy-19-like 1 (Dpy19l1), a homolog of C. elegans dpy-19, which encodes a putative multi-transmembrane protein shown to regulate directed migration of Q neuroblasts in C. elegans. At embryonic stages Dpy19l1 is highly expressed in glutamatergic neurons in the mouse cerebral cortex, whereas in the subpallium, where GABAergic neurons are generated, expression was below detectable levels. Downregulation of Dpy19l1 mediated by shRNA resulted in defective radial migration of glutamatergic neurons in vivo, which was restored by the expression of shRNA-insensitive Dpy19l1. Many Dpy19l1-knockdown cells were aberrantly arrested in the intermediate zone and the deep layer and, additionally, some extended single long processes towards the pial surface. Furthermore, we observed defective radial migration of bipolar cells in Dpy19l1-knockdown brains. Despite these migration defects, these cells correctly expressed Cux1, which is a marker for upper layer neurons, suggesting that Dpy19l1 knockdown results in migration defects but does not affect cell type specification. These results indicate that Dpy19l1 is required for the proper radial migration of glutamatergic neurons, and suggest an evolutionarily conserved role for the Dpy19 family in neuronal migration.

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  • Deficiency of mDia, an Actin Nucleator, Disrupts Integrity of Neuroepithelium and Causes Periventricular Dysplasia 査読

    Dean Thumkeo, Ryota Shinohara, Keisuke Watanabe, Hirohide Takebayashi, Yosuke Toyoda, Kiyoshi Tohyama, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya

    PLOS ONE   6 ( 9 )   e25465   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    During development of the central nervous system, the apical-basal polarity of neuroepithelial cells is critical for homeostasis of proliferation and differentiation of neural stem cells. While adherens junctions at the apical surface of neuroepithelial cells are important for maintaining the polarity, the molecular mechanism regulating integrity of these adherens junctions remains largely unknown. Given the importance of actin cytoskeleton in adherens junctions, we have analyzed the role of mDia, an actin nucleator and a Rho effector, in the integrity of the apical adherens junction. Here we show that mDia1 and mDia3 are expressed in the developing brain, and that mDia3 is concentrated in the apical surface of neuroepithelium. Mice deficient in both mDia1 and mDia3 develop periventricular dysplastic mass widespread throughout the developing brain, where neuroepithelial cell polarity is impaired with attenuated apical actin belts and loss of apical adherens junctions. In addition, electron microscopic analysis revealed abnormal shrinkage and apical membrane bulging of neuroepithelial cells in the remaining areas. Furthermore, perturbation of Rho, but not that of ROCK, causes loss of the apical actin belt and adherens junctions similarly to mDia-deficient mice. These results suggest that actin cytoskeleton regulated by Rho-mDia pathway is critical for the integrity of the adherens junctions and the polarity of neuroepithelial cells, and that loss of this signaling induces aberrant, ectopic proliferation and differentiation of neural stem cells.

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  • Macroglial Plasticity and the Origins of Reactive Astroglia in Experimental Autoimmune Encephalomyelitis 査読

    Fuzheng Guo, Yoshiko Maeda, Joyce Ma, Monica Delgado, Jiho Sohn, Laird Miers, Emily Mills Ko, Peter Bannerman, Jie Xu, Yazhou Wang, Chengji Zhou, Hirohide Takebayashi, David Pleasure

    JOURNAL OF NEUROSCIENCE   31 ( 33 )   11914 - 11928   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Accumulations of hypertrophic, intensely glial fibrillary acidic protein-positive (GFAP(+)) astroglia, which also express immunoreactive nestin and vimentin, are prominent features of multiple sclerosis lesions. The issues of the cellular origin of hypertrophic GFAP(+)/vimentin(+)/nestin(+) "reactive" astroglia and also the plasticities and lineage relationships among three macroglial progenitor populations-oligodendrocyte progenitor cells (OPCs), astrocytes and ependymal cells-during multiple sclerosis and other CNS diseases remain controversial. We used genetic fate-mappings with a battery of inducible Cre drivers (Olig2-Cre-ERT2, GFAP-Cre-ERT2, FoxJ1-Cre-ERT2 and Nestin-Cre-ERT2) to explore these issues in adult mice with myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis (EAE). The proliferative rate of spinal cord OPCs rose fivefold above control levels during EAE, and numbers of oligodendroglia increased as well, but astrogenesis from OPCs was rare. Spinal cord ependymal cells, previously reported to be multipotent, did not augment their low proliferative rate, nor give rise to astroglia or OPCs. Instead, the hypertrophic, vimentin(+)/nestin(+), reactive astroglia that accumulated in spinal cord in this multiple sclerosis model were derived by proliferation and phenotypic transformation of fibrous astroglia in white matter, and solely by phenotypic transformation of protoplasmic astroglia in gray matter. This comprehensive analysis of macroglial plasticity in EAE helps to clarify the origins of astrogliosis in CNS inflammatory demyelinative disorders.

    DOI: 10.1523/JNEUROSCI.1759-11.2011

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  • Evidence for the spontaneous production but massive programmed cell death of new neurons in the subcallosal zone of the postnatal mouse brain 査読

    Woon Ryoung Kim, Sung Kun Chun, Tae Woo Kim, Hyun Kim, Katsuhiko Ono, Hirohide Takebayashi, Kazuhiro Ikenaka, Ronald W. Oppenheim, Woong Sun

    EUROPEAN JOURNAL OF NEUROSCIENCE   33 ( 4 )   599 - 611   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    In the last 10 years, many studies have reported that neural stem/progenitor cells spontaneously produce new neurons in a subset of adult brain regions, including the hippocampus, olfactory bulb (OB), cerebral cortex, substantia nigra, hypothalamus, white matter and amygdala in several mammalian species. Although adult neurogenesis in the hippocampus and OB has been clearly documented, its occurrence in other brain regions is controversial. In the present study, we identified a marked accumulation of new neurons in the subcallosal zone (SCZ) of Bax-knockout mice in which programmed cell death (PCD) of adult-generated hippocampal and OB neurons has been shown to be completely prevented. By contrast, in the SCZ of wild-type (WT) mice, only a few immature (but no mature) newly generated neurons were observed, suggesting that virtually all postnatally generated immature neurons in the SCZ were eliminated by Bax-dependent PCD. Treatment of 2-month-old WT mice with a caspase inhibitor, or with the neurotrophic factor brain-derived neurotrophic factor, promoted the survival of adult-generated neurons, suggesting that it is the absence of sufficient neurotrophic signaling in WT SCZ that triggers the Bax-dependent, apoptotic PCD of newly generated SCZ neurons. Furthermore, following focal traumatic brain injury to the posterior brain, SCZ neurogenesis in WT mice was increased, and a subset of these newly generated neurons migrated toward the injury site. These data indicate that the adult SCZ maintains a neurogenic potential that could contribute to recovery in the brain in response to the injury-induced upregulation of neurotrophic signaling.

    DOI: 10.1111/j.1460-9568.2010.07557.x

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  • Genetically-defined lineage tracing of Nkx2.2-expressing cells in chick spinal cord 査読

    Hitoshi Gotoh, Katsuhiko Ono, Hirohide Takebayashi, Hidekiyo Harada, Harukazu Nakamura, Kazuhiro Ikenaka

    DEVELOPMENTAL BIOLOGY   349 ( 2 )   504 - 511   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    In the spinal cord, generation of oligodendrocytes (OLs) is totally dependent on the presence of Olig2, a basic helix-loop-helix transcription factor. However, it also requires Nkx2.2 for its generation, whose expression follows the expression of Olig2. Although it is believed that oligodendrocytes originate from the pMN domain. Nkx2.2 is present in the p3 domain located ventral to the pMN domain. According to recent reports, it is possible that oligodendrocytes are directly derived from the p3 domain in addition to the pMN domain in the chick spinal cord. We examined this hypothesis in this paper.
    To analyze OL development in the spinal cord, chick embryos are widely used for genetic modification by electroporation or for transplantation experiments, because it is relatively easy to manipulate them compared with mouse embryos. However, genetic modification by electroporation is not appropriate for glial development analyses because glia proliferate vigorously before maturation. In order to overcome these problems, we established a novel method to permanently introduce exogenous gene into a specific cell type. We introduced the CAT1 gene, a murine retroviral receptor, by electroporation followed by injection of murine retrovirus. By using this method, we successfully transduced murine retrovirus into the chick neural tube. We analyzed cell lineage from the p3 domain by restricting CAT1 expression by Nkx2.2-enhancer and found that most of the labeled cells became OLs when the cells were labeled at cE4. Moreover, the labeled OLs were found throughout the white matter in the spinal cord including the most dorsal spinal cord. Thus p3 domain directly generates spinal cord OLs in the chick spinal cord. (C) 2010 Elsevier Inc. All rights reserved.

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  • Roles of mDia isoforms, a Rho effector, in neuroblast migration 査読

    Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Keisuke Watanabe, Hirohide Takebayashi, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya

    JOURNAL OF PHARMACOLOGICAL SCIENCES   115   133P - 133P   2011年

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    記述言語:英語   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • Olig2 Lineage Cells Generate GABAergic Neurons in the Prethalamic Nuclei, Including the Zona Incerta, Ventral Lateral Geniculate Nucleus and Reticular Thalamic Nucleus 査読

    Naoko Inamura, Katsuhiko Ono, Hirohide Takebayashi, Bernard Zalc, Kazuhiro Ikenaka

    DEVELOPMENTAL NEUROSCIENCE   33 ( 2 )   118 - 129   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    Neuronal differentiation is a crucial event during neural development. Recent studies have characterized the development of the diencephalon; however, the origins of the primarily GABAergic prethalamic nuclei, including the zona incerta (ZI), ventral lateral geniculate nucleus (vLG) and reticular thalamic nucleus (RT), remain unclear. Here we characterize Olig2 lineage cells in the developing prethalamus using mice in which tamoxifen-induced recombination permanently labels Olig2-expressing cells. We show that GABAergic neurons in the prethalamic nuclei, including the RT, ZI and vLG, originate from prethalamic Olig2 lineage cells. Based on these data and on those derived from short-term lineage-tracing data using Olig3-lacZ mice and previous reports, we suggest that vLG cells originate from the ventricular zone of the thalamus, zona limitans intrathalamica and prethalamus. Copyright (C) 2011 S. Karger AG, Basel

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  • mDia, an actin nucleator and a Rho effector, is critical for tangential migration of cortical and olfactory bulb inhibitory interneuron precursors 査読

    Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Keisuke Watanabe, Hirohide Takebayashi, Hiroshi Kiyonari, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya

    NEUROSCIENCE RESEARCH   71   E130 - E130   2011年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2011.07.556

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  • Origin of New Glial Cells in Intact and Injured Adult Spinal Cord 査読

    Fanie Barnabe-Heider, Christian Goritz, Hanna Sabelstrom, Hirohide Takebayashi, Frank W. Pfrieger, Konstantinos Meletis, Jonas Frisen

    CELL STEM CELL   7 ( 4 )   470 - 482   2010年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Several distinct cell types in the adult central nervous system have been suggested to act as stem or progenitor cells generating new cells under physiological or pathological conditions. We have assessed the origin of new cells in the adult mouse spinal cord by genetic fate mapping. Oligodendrocyte progenitors self-renew, give rise to new mature oligodendrocytes, and constitute the dominating proliferating cell population in the intact adult spinal cord. In contrast, astrocytes and ependymal cells, which are restricted to limited self-duplication in the intact spinal cord, generate the largest number of cells after spinal cord injury. Only ependymal cells generate progeny of multiple fates, and neural stem cell activity in the intact and injured adult spinal cord is confined to this cell population. We provide an integrated view of how several distinct cell types contribute in complementary ways to cell maintenance and the reaction to injury.

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  • Roles of mDia isoforms, a Rho effector, in neural development 査読

    Ryota Shinohara, Dean Thumkeo, Hiroshi Kamijo, Naoko Kaneko, Kazunobu Sawamoto, Hiroyuki Hioki, Takeshi Kaneko, Keisuke Watanabe, Hirohide Takebayashi, Toshimasa Ishizaki, Tomoyuki Furuyashiki, Shuh Narumiya

    NEUROSCIENCE RESEARCH   68   E138 - E138   2010年

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2010.07.2184

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  • Olig2 transcription factor in the developing and injured forebrain; cell lineage and glial development 査読

    Katsuhiko Ono, Hirohide Takebayashi, Kazuhiro Ikenaka

    MOLECULES AND CELLS   27 ( 4 )   397 - 401   2009年4月

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    記述言語:英語   出版者・発行元:KOREAN SOC MOLECULAR & CELLULAR BIOLOGY  

    Olig2 transcription factor is widely expressed throughout the central nervous system; therefore, it is considered to have multiple functions in the developing, mature and injured brain. In this mini-review, we focus on Olig2 in the forebrain (telencephalon and diencephalon) and discuss the functional significance of Olig2 and the differentiation properties of Olig2-expressing progenitors in the development and injured states. Short- and long-term lineage analysis in the developing forebrain elucidated that not all late Olig2+ cells are direct cohorts of early cells and that Olig2 lineage cells differentiate into neurons or glial cells in a region- and stage-dependent manner. Olig2-deficient mice revealed large elimination of oligodendrocyte precursor cells and a decreased number of astrocyte progenitors in the dorsal cortex, whereas no reduction in the number of GABAergic neurons. In addition to Olig2 function in the developing cortex, Olig2 is also reported to be important for glial scar formation after injury. Thus, Olig2 can be essential for glial differentiation during development and after injury.

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  • Genetic Fate Mapping of Olig2 Progenitors in the Injured Adult Cerebral Cortex Reveals Preferential Differentiation Into Astrocytes 査読

    Kouko Tatsumi, Hirohide Takebayashi, Takayuki Manabe, Kenji F. Tanaka, Manabu Makinodan, Takahira Yamauchi, Eri Makinodan, Hiroko Matsuyoshi, Hiroaki Okuda, Kazuhiro Ikenaka, Akio Wanaka

    JOURNAL OF NEUROSCIENCE RESEARCH   86 ( 16 )   3494 - 3502   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Olig2 is a basic helix-loop-helix (bHLH) transcription factor essential for development of motoneurons and oligodendrocytes. It is known that Olig2(+) cells persist in the central nervous system (CNS) from embryonic to adult stages and that the number of Olig2+ progenitors increases in the injured adult CNS. Recent studies have demonstrated an inhibitory action of Olig2 on neurogenesis in adult CNS, but the fate of Olig2(+) cells in the injured state remains largely unknown. To trace directly the fate of Olig2 cells in the adult cerebral cortex after injury, we employed the CreER/loxP system to target the olig2 locus. In this genetic tracing study, green fluorescent protein (GFP) reporter-positive cells labeled after cryoinjury coexpressed glial fibrillary acidic protein (GFAP), an astrocytic marker. Electron microscopy also showed that GFP(+) cells have the ultrastructural characteristics of astrocytes. Furthermore, GFP(+) cells labeled before injury, most of which had been NG2 cells, also produced bushy astrocytes. Here we show direct evidence that Olig2(+) cells preferentially differentiate into astrocytes, which strongly express GFAP, in response to injury in the adult cerebral cortex. These results suggest that reactive astrocytes, known to be the main contributors to glial scars, originate, at least in part, from Olig2(+) cells. (c) 2008 Wiley-Liss, Inc.

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  • Tamoxifen Modulates Apoptosis in Multiple Modes of Action in CreER Mice 査読

    Hirohide Takebayashi, Noriyoshi Usui, Katsuhiko Ono, Kazuhiro Ikenaka

    GENESIS   46 ( 12 )   775 - 781   2008年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Tamoxifen-inducible Cre (CreER) has become a powerful tool for in vivo manipulation of the genome. Here, we investigated opposing effects of tamoxifen on apoptosis during embryogenesis using Olig2-CreER knock-in mice, namely, tamoxifen-induced apoptosis through CreER-mediated toxicity and cytoprotective activity of tamoxifen independent of CreER. First, we examined tamoxifen-induced apoptosis; in the homozygous mice, we observed region-specific apoptosis in the ventral neural tube, with no obvious increase in the heterozygotes. Next, we detected a cytoprotective effect on apoptosis in the homozygous dorsal root ganglia (DRG). This apoptosis is a secondary phenotype of Olig2-null mice, as Olig2/CreER is not expressed in the DRG. The cytoprotective effect is DRG-specific, because tamoxifen did not rescue apoptosis in the interdigital mesenchyme. These data indicate that tamoxifen has multiple effects on apoptosis during development and caution that careful examination is necessary when interpreting results obtained from tamoxifen-induced recombination: in Olig2-CreER mice, heterozygotes are usable for lineage-tracing experiment without obvious toxicity, while homozygotes show efficient recombination, despite enhanced apoptosis. genesis 46:775-781, 2008. (C) 2008 Wiley-Liss, Inc.

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  • Progeny of Olig2-Expressing Progenitors in the Gray and White Matter of the Adult Mouse Cerebral Cortex 査読

    Leda Dimou, Christiane Simon, Frank Kirchhoff, Hirohide Takebayashi, Magdalena Goetz

    JOURNAL OF NEUROSCIENCE   28 ( 41 )   10434 - 10442   2008年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Despite their abundance, still little is known about the rather frequent, constantly proliferating progenitors spread throughout the adult mouse brain parenchyma. The majority of these progenitors express the basic-helix-loop-helix transcription factor Olig2, and their number further increases after injury. Here, we examine the progeny of this progenitor population by genetic fate mapping using tamoxifen-inducible Cre-recombination in the Olig2 locus to turn on permanent reporter gene expression in the adult brain. Consistent with Olig2 expression in proliferating NG2(+) progenitors, most reporter (+) cells seen shortly after initiating recombination at adult stages incorporated BrdU and contained the proteoglycan NG2 in both the gray (GM) and the white matter (WM) of the cerebral cortex. However, at longer time points after induction, we observed profound differences in the identity of reporter (+) cells in the WM and GM. Whereas most of the Olig2 (+) progenitors had generated mature, myelinating oligodendrocytes in the WM, hardly any reporter (+) cells showing mature oligodendrocyte characteristics were detectable even up to 6 months after recombination in the GM. In the GM, most reporter (+) cells remained NG2(+), even after injury, but stopped proliferating rather soon after recombination. Thus, our results demonstrate the continuous generation of mature, myelinating oligodendrocytes in the WM, whereas cells in the GM generated mostly postmitotic NG2 (+) glia.

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  • Regional- and temporal-dependent changes in the differentiation of Olig2 progenitors in the forebrain, and the impact on astrocyte development in the dorsal pallium 査読

    Katsuhiko Ono, Hirohide Takebayashi, Kazuyo Ikeda, Miki Furusho, Takumi Nishizawa, Keisuke Watanabe, Kazuhiro Ikenaka

    DEVELOPMENTAL BIOLOGY   320 ( 2 )   456 - 468   2008年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Olig2 is a basic helix-loop-helix transcription factor essential for oligodendrocyte and motoneuron development in the spinal cord. Olig2-positive (Olig2+) cells in the ventricular zone of the ventral telencephalon have been shown to differentiate into GABAergic and cholinergic neurons. However, the fate of Olig2 lineage cells in the postnatal forebrain has not been fully described and Olig2 may regulate the development of both astrocytes and oligodendrocytes. Here, we examined the fate of embryonic Olig2+ progenitors using a tamoxifen-inclucible CFe/loxP system. Using long-term lineage tracing, Olig2+ cells in the early fetal stage primarily differentiated into GABAergic neurons in the adult telencephalon, while those in later Stages gave rise to macroglial cells, both astrocytes and oligodendrocytes. Olig2+ progenitors in the diencephalon developed into oligodendrocytes, as observed in the spinal cord, and a fraction developed into glutamatergic neurons. Olig2 lineage oligodendrocytes tended to form clusters, probably due to local proliferation at the site of terminal differentiation. In spite of the abundance of Olig2 lineage GABAergic neurons in the normal neocortex, GABAergic neurons seemed to develop at normal density in the Olig2 deficient mouse. Thus, Olig2 is dispensable for GABAergic neuron specification. In contrast, at the late fetal stage in the Olig2 deficient mouse, astrocyte development was retarded in the dorsal neocortex, but not in the basal forebrain. Olig2 functions, therefore, in gliogenesis in the dorsal pallium. Short-term lineage tracing experiments revealed that the majority of late Olig2+ cells were not direct descendants of early Olig2+ progenitors in the fetal forebrain. These observations indicate that embryonic Olig2+ progenitor cells change their differentiative properties during development, and also that Olig2 plays a role in astrocyte development in a region-specific manner. (C) 2008 Elsevier Inc. All rights reserved.

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  • Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic olig2-expressing precursors 査読

    Goichi Miyoshi, Simon J. B. Butt, Hirohide Takebayashi, Gord Fishell

    JOURNAL OF NEUROSCIENCE   27 ( 29 )   7786 - 7798   2007年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Inhibitory GABAergic interneurons of the mouse neocortex are a highly heterogeneous population of neurons that originate from the ventral telencephalon and migrate tangentially up into the developing cortical plate. The majority of cortical interneurons arise from a transient embryonic structure known as the medial ganglionic eminence (MGE), but how the remarkable diversity is specified in this region is not known. We have taken a genetic fate mapping strategy to elucidate the temporal origins of cortical interneuron subtypes within the MGE. We used an inducible form of Cre under the regulation of Olig2, a basic helix-loop-helix transcription factor highly expressed in neural progenitors of the MGE. We observe that the physiological subtypes of cortical interneurons are, to a large degree, unique to their time point of generation.

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  • Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance 査読

    Kenji F. Tanaka, Hirohide Takebayashi, Yoshihiko Yamazaki, Katsuhiko Ono, Masae Naruse, Takuji Iwasato, Shigeyoshi Itohara, Hiroshi Kato, Kazuhiro Ikenaka

    GLIA   55 ( 6 )   617 - 631   2007年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark is the formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist of GFAP and several heat shock proteins. The presence of mutant GFAP would appear to be involved in RF formation; however, overproduction of wild type human GFAP in mouse brain also results in RF formation. Here, we investigated the in vivo conditions leading to formation of RF-like aggregates. We used transgenic mice (mouse GFAP promoter-human GFAP cDNA with R239H mutation) in which the dosage of the GFAP transgene could be manipulated within the same genetic locus. We found that the presence of mutant GFAP per se was insufficient for aggregate formation. Instead, a 30% increase in GFAP content over that in wild type was also required. GFAP aggregates upregulated endogenous GFAP and nestin gene expression, and intermediate filament structure revealed by immunostaining was fragmented under these conditions. However, overall morphology of astrocytes, including their fine processes, was unaffected. In this transgenic animal model, mice did not show megalencephaly, leukodystrophy, or seizure characteristic of Alexander disease with R239H mutation. Nevertheless, their mortality after kainate challenge was dramatically increased, whereas transgenic mice lacking aggregates exhibited mortality similar to that of wild type mice. These results indicate that the presence of GFAP aggregates containing mutant GFAP is not sufficient to induce a major phenotype of Alexander disease, even though it causes some abnormalities in the mouse. (c) 2007 Wiley-Liss, Inc.

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  • NG2 and Olig2 expression provides evidence for phenotypic deregulation of cultured central nervous system and peripheral nervous system neural precursor cells 査読

    Cecile Dromard, Sylvain Bartolami, Loic Deleyrolle, Hirohide Takebayashi, Chantal Ripoli, Lionel Simonneau, Sylvie Prome, Sylvie Puech, Christophe Tran Van Ba, Christophe Duperray, Jean Valmier, Alain Privat, Jean-Philippe Hugnot

    STEM CELLS   25 ( 2 )   340 - 353   2007年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ALPHAMED PRESS  

    Neural stem cells cultured with fibroblast growth factor 2 (FGF2)/epidermal growth factor (EGF) generate clonal expansions called neurospheres (NS), which are widely used for therapy in animal models. However, their cellular composition is still poorly defined. Here, we report that NS derived from several embryonic and adult central nervous system (CNS) regions are composed mainly of remarkable cells coexpressing radial glia markers (BLBP, RC2, GLAST), oligodendrogenic/neurogenic factors (Mash1, Olig2, Nkx2.2), and markers that in vivo are typical of the oligodendrocyte lineage (NG2, A2B5, PDGFR-alpha). On NS differentiation, the latter remain mostly expressed in neurons, together with Olig2 and Mash1. Using cytometry, we show that in growing NS the small population of multi-potential self-renewing NS-forming cells are A2B5(+) and NG2(+). Additionally, we demonstrate that these NS-forming cells in the embryonic spinal cord were initially NG2(-) and rapidly acquired NG2 in vitro. NG2 and Olig2 were found to be rapidly induced by cell culture conditions in spinal cord neural precursor cells. Olig2 expression was also induced in astrocytes and embryonic peripheral nervous system (PNS) cells in culture after EGF/FGF treatment. These data provide new evidence for profound phenotypic modifications in CNS and PNS neural precursor cells induced by culture conditions.

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  • Regulation of glial development by cystatin C 査読

    Akiko Hasegawa, Masae Naruse, Seiji Hitoshi, Yasuno Iwasaki, Hirohide Takebayashi, Kazuhiro Ikenaka

    JOURNAL OF NEUROCHEMISTRY   100 ( 1 )   12 - 22   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    Cystatin C (CysC) is an endogenous cysteine proteases inhibitor produced by mature astrocytes in the adult brain. Previously we isolated CysC as a factor activating the glial fibrillary acidic protein (GFAP) promoter, and showed that CysC is expressed in astrocyte progenitors during development. Here we show that protease inhibitor activity increased daily in conditioned medium, and that this activity was mainly a result of CysC released from primary cultured cells. Human CysC added to the culture medium of primary brain cells increased the number of GFAP-positive and nestin-positive cells. Human CysC also increased the number of neurospheres formed from embryonic brain, and thus it increases the number of neural stem/precursor cells in a manner similar to glycosylated rat CysC. The addition of a neutralizing antibody, on the other hand, greatly decreased the number of GFAP and glutamate aspartate transporter (GLAST)-positive astrocytes. This decrease was reversed by the addition of CysC but not by another cysteine protease inhibitor. Thus, the promotion of astrocyte development by CysC appears to be independent of its protease inhibitor activity. The antibody increased the number of oligodendrocytes and their precursors. Therefore, CysC modifies glial development in addition to its activity against neural stem/precursor cells.

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  • Expression of the basic helix-loop-factor Olig2 in the developing retina: Olig2 as a new marker for retinal progenitors and late-born cells 査読

    Koi Shibasaki, Hirohide Takebayashi, Kazuhiro Ikenaka, Liang Feng, Lin Gan

    GENE EXPRESSION PATTERNS   7 ( 1-2 )   57 - 65   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    In this study, we examined the spatiotemporal expression patterns of Olig2, a basic helix-loop-helix transcription factor, in the developing mouse retina. Expression of Olig2 was initially detected on embryonic day 12.5 (E12.5). The majority of Olig2-positive cells were identified as retinal progenitor cells throughout embryogenesis. During later embryonic stages, the number of Olig2-positive retinal progenitor cells increased, and Olig2-positive cells were confined only to the neuroblast layer (NBL). Olig2 expression was not observed in the ganglion cell layer (GCL) nor in the inner nuclear layer (INL) that contain the differentiated retinal cell types, indicating that Olig2 is not expressed in differentiated cells in prenatal retina. In later postnatal stages, Olig2 expression was retained in mature neurons and glial cells, namely retinal ganglion cells (RGCs), amacrine cells (ACs), horizontal cells, bipolar cells and Muller glial cells. Thus, Olig2 is an marker both for retinal progenitor cells during embryonic stages, and also for differentiated retinal subpopulations within the GCL and INL during postnatal stages. (c) 2006 Elsevier B.V. All rights reserved.

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  • Involvement of the Olig2 transcription factor in cholinergic neuron development of the basal forebrain 査読

    M Furusho, K Ono, H Takebayashi, N Masahira, T Kagawa, K Ikeda, K Ikenaka

    DEVELOPMENTAL BIOLOGY   293 ( 2 )   348 - 357   2006年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Cholinergic neurons, which express choline acetyltransferase (ChAT), are a major neuron subset generated in the basal forebrain. Areas presumed to be sites of origin of cholinergic neurons are roughly demarcated by expression of Olig2, a basic helix-loop-helix transcription factor, which includes the medial ganglionic eminence, septal area, and anterior entopeduncular/preoptic area. In the present study, we examined the involvement of Olig2 in cholinergic differentiation. When the Olig2-expressing cells at E12.5 were permanently modified to express the lacZ or EGFP gene by tamoxifen-induced Cre-mediated recombination, the cells marked by reporter gene expression were widely distributed in the basal forebrain by E18.5, some of which expressed neuronal markers. We showed that a small number of cells were double-positive for ChAT and X-gal or EGFP in almost all cases. In addition, the number of ChAT+ cells was reduced to 60% in the Olig2 knockout mouse basal forebrain. No evidence of elevated apoptosis or reduced proliferation was observed in the knockout mouse forebrain. The present study provides the first direct evidence for involvement of the Olig2 gene in cholinergic differentiation in the basal forebrain. (c) 2006 Elsevier Inc. All rights reserved.

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  • Olig2-positive progenitors in the embryonic spinal cord give rise not only to motoneurons and oligodendrocytes, but also to a subset of astrocytes and ependymal cells 査読

    N Masahira, H Takebayashi, K Ono, K Watanabe, L Ding, M Furusho, Y Ogawa, Y Nabeshima, A Alvarez-Buylla, K Shimizu, K Ikenaka

    DEVELOPMENTAL BIOLOGY   293 ( 2 )   358 - 369   2006年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Motoneurons and oligodendrocytes in the embryonic spinal cord are produced from a restricted domain of the ventral ventricular zone, termed the pMN domain. The pMN domain is the site of expression of two basic helix-loop-helix transcription factors, Olig1 and Olig2, which are essential for motoneuron and oligodendrocyte development. Previous lineage-tracing experiments using Olig1-Cre and Olig2-GFP mice suggested that motoneurons and oligodendrocytes, but not astrocytes, are produced from the pMN domain. However, important questions remain, including the fate of neuroepithelial cells in the pMN domain, and specifically whether motoneurons and oligodendrocytes are the only types of cells produced in the pMN domain. We performed lineage-tracing experiments using a tamoxifen-inducible Cre-recombinase inserted into the Olig2 locus. We demonstrated that motoneurons and oligodendrocyte progenitors are derived from the Olig2(+) progenitors in the pMN domain, and also found that a subset of astrocytes at the ventral surface of the spinal cord and ependymal cells at the ventricular surface are also produced from the pMN domain. These findings demonstrate that motoneurons and oligodendrocytes are not the only cell types originating from this domain. (c) 2006 Elsevier Inc. All rights reserved.

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  • Basic fibroblast growth factor endows dorsal telencephalic neural progenitors with the ability to differentiate into oligodendrocytes but not gamma-aminobutyric acidergic neurons 査読

    M Abematsu, T Kagawa, S Fukuda, T Inoue, H Takebayashi, S Komiya, T Taga

    JOURNAL OF NEUROSCIENCE RESEARCH   83 ( 5 )   731 - 743   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Basic fibroblast growth factor (bFGF) is commonly used to enrich and maintain neural stem cells in vitro. Olig2 is an essential transcription factor for oligodendrocyte lineage specification and is expressed predominantly in ventral neuroepithelial cells in the medial and lateral ganglionic eminence (GE), where oligodendrocyte progenitors originate. Here we report significant induction of Olig2 expression in dorsal neuroepithelium-derived cells cultured in the presence of bFGF, in which Olig2-expressing cells were initially negligible. Among Olig2-expressing cells appearing after a 5-day treatment with bFGF, 99.8% coexpressed nestin. There was no significant difference in proliferation or apoptosis in dorsal and ventral neuroepithelial cultures in the presence of bFGF, suggesting that bFGF induces ectopic expression of Olig2 in dorsal "cortical" neuroepithelial cells. Similarly, expression of Mash1, another ventral neuroepithelial cell marker gene, was also induced in cultured dorsal neuroepithelial cells in the presence of bFGF Conversely, in this culture, expression of dorsal neuroepithelial cell markers, such as Neurogenin1, Neurogenin2, Pax6, and Emx2, was downregulated. These results suggested a possible ventralizing activity of bFGF. In fact, bFGF-treated dorsal neuroepithelial cells acquired the potential to generate O4-positive oligodendrocytes with efficacy comparable to that observed with GE-derived cells. In marked contrast, bFGF did not enable dorsal neuroepithelial cells to generate gamma-aminobutyric acid (GABA) neurons, which normally develop only from GE in vivo. Thus, bFGF endows dorsal telencephalic neural progenitors with the ability to differentiate into oligodendrocytes but not GABAergic neurons, suggesting the presence of different mechanisms governing specification of dorsoventral cell identities of neuronal and glial cell lineages. (C) 2006 Wiley-Liss, Inc.

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  • In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis 査読

    DA Lim, M Suarez-Farinas, F Naef, CR Hacker, B Menn, H Takebayashi, M Magnasco, N Patil, A Alvarez-Buylla

    MOLECULAR AND CELLULAR NEUROSCIENCE   31 ( 1 )   131 - 148   2006年1月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Neural stem cells and neurogenesis persist in the adult mammalian brain subventricular zone (SVZ). Cells born in the rodent SVZ migrate to the olfactory bulb (Ob) where they differentiate into interneurons. To determine the gene expression and functional profile of SVZ neurogenesis, we performed three complementary sets of transcriptional analysis experiments using Affymetrix GeneChips: (1) comparison of adult mouse SVZ and Ob gene expression profiles with those of the striatum, cerebral cortex, and hippocampus; (2) profiling of SVZ stem cells and ependyma isolated by fluorescent-activated cell sorting (FRCS); and (3) analysis of gene expression changes during in vivo SVZ regeneration after antimitotic treatment. Gene Ontology (GO) analysis of data from these three separate approaches showed that in adult SVZ neurogenesis, RNA splicing and chromatin remodeling are biological processes as statistically significant as cell proliferation, transcription, and neurogenesis. In non-neurogenic brain regions, RNA splicing and chromatin remodeling were not prominent processes. Fourteen mRNA splicing factors including Sf3b1, Sfrs2, Lsm4, and Khdrbs1/Sam68 were detected along with 9 chromatin remodeling genes including Mll, Bmi1, Smarcad1, Baf53a, and Hall. We validated the transcriptional profile data with Northern blot analysis and in situ hybridization. The data greatly expand the catalogue of cell cycle components, transcription factors, and migration genes for adult SVZ neurogenesis and reveal RNA splicing and chromatin remodeling as prominent biological processes for these germinal cells. (C) 2005 Elsevier Inc. All rights reserved.

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  • An animal model for late onset chronic demyelination disease caused by failed terminal differentiation of oligodendrocytes 査読

    JM Ma, M Matsumoto, KF Tanaka, H Takebayashi, K Ikenaka

    NEURON GLIA BIOLOGY   2 ( 2 )   81 - 91   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CAMBRIDGE UNIV PRESS  

    Various animal models are available for studying human multiple sclerosis (MS). Most of them model the initial phase of MS, including the immune-triggered attack of the myelin membrane and/or oligodendrocytes and, occasionally, demonstrate the remission and relapsing phases. However, few mimic the late chronic demyelinating phase. Overexpression of the proteolipid protein gene (Plp) causes a unique demyelinating disorder in mice in which normal-appearing mlyelin forms early in life and chronic demyelination occurs later. We found that remyelination is severely affected in this late demyelinating phase, but is not caused by deprivation of oligodendrocyte progenitors expressing PDGF receptor alpha (PDGFR alpha) and Olig2, which are present at an even higher number in the demyelinated white matter of the mutants than in wild-type controls. Furthermore, mature oligodendrocytes containing PLP were observed, but failed to remyelinate. The ability of oligodendrocytes from older transgenic annuals to produce a myelin membrane-like structure was not impaired when cultured in vitro, which indicates that the lack of remyelination is not simply caused by changes in the intrinsic properties of the oligodendrocytes. Glial activation also occurred much earlier than active demyelination in mutant mice. Thus, in addition to intrinsic mechanisms, extrinsic mechanisms might also have an important role in defects of remyelination. These features are also observed ill patients at a late stage of MS, leading to chronic demyelinating lesions. Thus, this mouse model partly mimics the late stage of MS and can be used to study the cause of inhibition of remyelination.

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  • Short-term lineage analysis of dorsally derived Olig3 cells in the developing spinal cord 査読

    L Ding, H Takebayashi, K Watanabe, T Ohtsuki, KF Tanaka, Y Nabeshima, O Chisaka, K Ikenaka, K Ono

    DEVELOPMENTAL DYNAMICS   234 ( 3 )   622 - 632   2005年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    We examined the migration and differentiation of cells expressing Olig3, a basic helix-loop-helix transcriptional factor, in the developing spinal cord. Distribution of Olig3 lineage cells was demonstrated with in situ hybridization and X-gal staining in an Olig3-lacZ knock-in mouse. Olig3-positive cells first appeared in the dorsal spinal cord, except for the roof plate. Some of the dorsal Olig3 lineage cells co-expressed Islet1/2, Math1, or Brn3a, markers for dorsal interneuron. LacZ-positive cells were observed in the ventral-most part of the E10.5 spinal cord, suggesting that some dorsal Olig3 lineage cells migrate into the ventral-most part by E10.5. Ventral-ward migration of dorsal cells and contribution to commissural interneurons were substantiated by electroporation of EGFP expression plasmid in the dorsal spinal cord of chick embryo. Dorsal midline cells were also LacZ-positive during development. These findings suggest that dorsal Olig3 cells contribute to dorsal midline cells and commissural interneurons at intermediate and ventral levels.

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  • Improved preservation of X-gal reaction product for electron microscopy using hydroxypropyl methacrylate 査読

    N Masahira, L Ding, H Takebayashi, K Shimizu, K Ikenaka, K Ono

    NEUROSCIENCE LETTERS   374 ( 1 )   17 - 20   2005年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    In lineage tracing analysis, the beta-galactosidase (P-gal) gene is a commonly used as a reporter gene because it is relatively stable and highly sensitive in histochemical detection using 5-bromo-4-chloro-3-indolyl-beta-D-galactoside (X-gal). Clear determination of the types and characteristics of labeled cells requires transmission electron microscopic (TEM) examination of their morphology. X-gal staining, which involves the precipitate formed by the reaction between P-gal and X-gal, is usually recognized as a light blue or green reaction product on light microscopic (LM) examination. However, the standard protocol for TEM preparation weakens the intensity of or results in the loss of X-gal reaction product at the step of substitution of ethanol with Epon using propylene oxide. To solve this problem, we show that hydroxypropyl methacrylate achieves good preservation of X-gal reaction products. The protocol presented here appears to be useful for lineage determination by TEM of all types of X-gal-stained tissues. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

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  • Gliogenic radial glial cells show heterogeneity in the developing mouse spinal cord 査読

    Y Ogawa, H Takebayashi, M Takahashi, N Osumi, Y Iwasaki, K Ikenaka

    DEVELOPMENTAL NEUROSCIENCE   27 ( 6 )   364 - 377   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    The central nervous system of the mammalian embryo is organized according to the expression of region-specific transcription factors along the anteroposterior and/or the dorsoventral axis. For example, the dorsal ventricular zone (VZ) of the embryonic spinal cord expresses Pax3 and Pax7, the ventral VZ expresses Pax6, and the more ventral VZ expresses Nkx2.2. Properties of neuronal precursors located in the VZ are determined by the characteristic expression patterns of these transcription factors, leading to the generation of distinct classes of neurons. Recent studies demonstrated that radial glial cells produce neurons in addition to glia during central nervous system development. Thus, neuronal precursor diversity may be dependent upon the diversity of radial glial cells. To investigate this hypothesis, we analyzed the expression of radial glial cell markers and transcription factors in the mouse embryonic spinal cord. We show that radial glial cells indeed express domain-specific transcription factor. Moreover, they varied in expression of the astrocyte-specific glutamate transporter. The region where the astrocyte-specific glutamate transporter is strongly expressed in the ventral radial glial cells is closely related to the Pax6-expressing domain, and the weakly expressing region corresponding to the Nkx2.2-expressing domain. Furthermore, dorsal radial fibers expressed ephrin-B1. Thus, different types of radial glial cells exist in different domains defined by the transcription factor expression at E12.5. We also show that this diversity continues to the gliogenic stage of radial glial cells. This raises the idea that astrocytes generated from different domains along the dorsoventral axis in the mouse spinal cord have distinct characteristics. Copyright (c) 2005 S. Karger AG, Basel.

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  • Converse control of oligodendrocyte and astrocyte lineage development by Sonic hedgehog in the chick spinal cord 査読

    E Agius, C Soukkarieh, C Danesin, P Kan, H Takebayashi, C Soula, P Cochard

    DEVELOPMENTAL BIOLOGY   270 ( 2 )   308 - 321   2004年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    In the developing spinal cord, oligodendrocyte progenitors (OLPs) originate from the ventral neuroepithelium and the specification of this lineage depends on the inductive activity of Sonic hedgehog (Shh) produced by ventral midline cells. On the other hand, it has been shown that OLP identity is acquired by the coexpression of the transcription factors olig2 and nka2.2. Although initially expressed in adjacent nonoverlapping domains of the ventral neuroepithelium, these transcription factors become coexpressed in the pMN domain at the time of OLP specification through dorsal extension of the Nkx2.2 domain. Here we show that Shh is sufficient to promote the coexpression of Olig2 and Nkx2.2 in neuroepithelial cells. In addition, Shh activity is necessary for this coexpression since blocking Shh signalling totally abolishes Olig2 expression and impedes dorsal extension of Nkx2.2. Although Shh at these stages affects neuroepithelial cell proliferation, the dorsal extension of the Nkx2.2 domain is not due to progenitor proliferation but to repatteming of the ventral neuroepithelium. Finally, Shh not only stimulates OLP specification but also simultaneously restricts the ventral extension of the astrocyte progenitor (AP) domain and reduces astrocyte development. We propose that specification of distinct glial lineages is the result of a choice that depends on Shh signalling. (C) 2004 Elsevier Inc. All rights reserved.

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  • Anti-human olig2 antibody as a useful immunohistochemical marker of normal oligodendrocytes and gliomas 査読

    H Yokoo, S Nobusawa, H Takebayashi, K Ikenaka, K Isoda, M Kamiya, A Sasaki, J Hirato, Y Nakazato

    AMERICAN JOURNAL OF PATHOLOGY   164 ( 5 )   1717 - 1725   2004年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC INVESTIGATIVE PATHOLOGY, INC  

    Olig2 is a recently identified transcription factor involved in the phenotype definition of cells in the oligodendroglial lineage. The expression of Olig2 transcript has been demonstrated in human oligodendroglial tumors, although the protein expression has not been studied extensively. We developed a polyclonal antibody to human Olig2 and analyzed it immunohistochemically. The antibody depicted a single distinct band of predicted molecular weight by Western blotting, and did not cross-react with human Olig1. in normal human brain tissue, the nuclei of oligodendrocytes of interfascicular, perivascular, and perineuronal disposition were clearly labeled by the antibody. Similarly, the nuclei of oligodendroglial tumors were labeled. There was no apparent correlation between the staining intensity and histological grade. Astrocytic components within the tumors were generally less or not stained. Astrocytic tumors were also positive with the Olig2 antiserum to a lesser extent, and the difference between oligodendroglial and astrocytic tumors was demonstrated by a statistical analysis. Olig2 and glial fibrillary acidic protein were expressed in a mutually exclusive manner, and Olig2 expression was cell-cycle related. Neither central neurocytoma nor schwannoma cases were stained. Our antibody was demonstrated to be useful in recognizing normal oligodendrocytes on paraffin sections, and applicable in diagnosis of some brain tumors.

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  • Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway 査読

    S Fukuda, T Kondo, H Takebayashi, T Taga

    CELL DEATH AND DIFFERENTIATION   11 ( 2 )   196 - 202   2004年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    In the developing vertebrate nervous system, multipotent neural stem cells produce both neurons and glia. OLIG2 is a basic helix-loop-helix transcription factor that plays critical roles in oligodendrocyte and motor neuron development; however, its role in astrocytic development remains elusive. In this study, we analyzed an effect of OLIG2 on cytokine-induced astrocytic differentiation from mouse telencephalic neuroepithelial cells. We show that the presence of OLIG2 protein leads to inhibition of the promoter activation of astrocyte-specific glial fibrillary acidic protein gene. We found that OLIG2 abolishes complex formation between a transcriptional coactivator p300 and a transcription factor, signal transducer and activator of transcription 3 (STAT3), which is activated by astrocytic differentiation-inducing cytokines, such as leukemia inhibitory factor (LIF). The enforced expression of OLIG2 in neuroepithelial cells inhibits the LIF-induced astrocytic differentiation. We also show that the OLIG2 protein in the nuclei of neural precursor cells disappears in accordance with astrocytic differentiation during culture with LIF. Together, these results reveal a novel molecular function of OLIG2 on the astrocyte development.

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  • The potential to induce glial differentiation is conserved between Drosophila and mammalian glial cells missing genes 査読

    Y Iwasaki, T Hosoya, H Takebayashi, Y Ogawa, Y Hotta, K Ikenaka

    DEVELOPMENT   130 ( 24 )   6027 - 6035   2003年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COMPANY OF BIOLOGISTS LTD  

    Drosophila glial cells missing (gcm) is a key gene that determines the fate of stem cells within the nervous system. Two mouse gcm homologs have been identified, but their function in the nervous system remains to be elucidated. To investigate their function, we constructed retroviral vectors harboring Drosophila gcm and two mouse Gcm genes. Expression of these genes appeared to influence fibroblast features. In particular, mouse Gcm1 induced the expression of astrocyte-specific Ca2+-binding protein, S100beta, in those cells. Introduction of the mouse Gcm1 gene in cultured cells from embryonic brains resulted in the induction of an astrocyte lineage. This effect was also observed by in utero injection of retrovirus harboring mouse Gcm1 into the embryonic brain. However, cultures from mouse Gcm1-deficient mouse brains did not exhibit significant reductions in the number of astrocytes. Furthermore, in situ hybridization analysis of mouse Gcm1 mRNA revealed distinct patterns of expression in comparison with other well-known glial markers. The mammalian homolog of Drosophila gcm, mouse Gcm1, exhibits the potential to induce gliogenesis, but may function in the generation of a minor subpopulation of glial cells.

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  • Evidence for a second wave of oligodendrogenesis in the postnatal cerebral cortex of the mouse 査読

    A Ivanova, E Nakahira, T Kagawa, A Oba, T Wada, H Takebayashi, N Spassky, J Levine, B Zalc, K Ikenaka

    JOURNAL OF NEUROSCIENCE RESEARCH   73 ( 5 )   581 - 592   2003年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    The existing view is that cortical oligodendrocytes (OLs) in rodents are born from the cortical subventricular zone (SVZ) after birth, but recent data suggest that many forebrain oligodendrocyte progenitor cells (OPCs) are specified much earlier (between E9.5 and E13.5 in the mouse) in the ventricular zone of the ventral forebrain under the control of sonic hedgehog (Shh) and migrate into the cortex afterward. We examined expression of specific early OL markers (PDGFRalpha, PLP/DM20, Olig2, and NG2) in the developing forebrain to clarify this issue. We propose that OPCs colonize the developing cortex in two temporally distinct waves. The gray matter is at least partially populated by a first wave of OPCs that arises in the medial ganglionic eminence and the entopeduncular area and spreads into the cortex via the developing cortical plate. The cerebral cortex benefits from the second wave of OPCs coming from residential SVZ. In the second wave, there might be two different types of precursor cells: PLP/DM20(+) cells populating only inner layers and PDGFRalpha(+) cells, which might eventually myelinate the outer regions as well. (C) 2003 Wiley-Liss, Inc.

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  • Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model 査読

    H Ding, P Shannon, N Lau, XL Wu, L Roncari, RL Baldwin, H Takebayashi, A Nagy, DH Gutmann, A Guha

    CANCER RESEARCH   63 ( 5 )   1106 - 1113   2003年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    A significant proportion of human malignant gliomas exhibit amplification, overexpression, or mutations of the epidermal growth factor receptor (EGFR). To define the functional role(s) of the EGFR in the pathogenesis of gliomas, we established transgenic mice that express both wild-type (wt) and mutant (EGFRvIII) EGFR molecules using the human glial fibrillary acidic protein (GFAP) promoter. Both GFAP-EGFR(wt) and GFAP-EGFRvIII transgenic mice demonstrated increased numbers of astrocytes compared with control littermates, however, developed normally without formation of gliomas. To determine whether EGFR overexpression could modify the tumor phenotype in our previously reported GFAP-V(12)Ha-ras transgenic mouse astrocytoma model, mice expressing both activated RAS and EGFR were developed. GFAP-V(12)Ha-ras;GFAP-EGFRvIII, but not GFAP-V(12)Ha-ras;GFAP-EGFR(wt) double transgenic mice, had decreased survival with fifty percent of the mice dead at 2-4 weeks from gliomas, compared with 12-16 weeks for the GFAP-V(12)Ha-ras mice. Furthermore, GFAP-V(12)Ha-ras;GFAP-EGFRvIII mice developed oligodendrogliomas and mixed oligoastrocytoma tumors, instead of the fibrillary astrocytomas observed in GFAP-V(12)Ha-ras mice. In addition to yielding a spontaneous model of infiltrating oligodendroglioma, this study demonstrates that astrocyte-specific expression of EGFRvIII alone is insufficient for gliomagenesis but rather contributes to glioma progression in the context of existing predisposing genetic changes.

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  • The basic helix-loop-helix factor Olig2 is essential for the development of motoneuron and oligodendrocyte lineages 査読

    H Takebayashi, Y Nabeshima, S Yoshida, O Chisaka, K Ikenaka, Y Nabeshima

    CURRENT BIOLOGY   12 ( 13 )   1157 - 1163   2002年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Sonic hedgehog (Shh), an organizing signal from ventral midline structures, is essential for the induction and maintenance of many ventral cell types in the embryonic neural tube. Olig1 and Olig2 are related basic helix-loop-helix factors induced by Shh in the ventral neural tube. Although expression analyses and gain-of-function experiments suggested that these factors were involved in motoneuron and oligodendrocyte development, they do not clearly define the functional differences between Olig1 and Olig2. We generated mice with a homozygous inactivation of Olig2. These mice did not feed and died on the day of birth. In the spinal cord of the mutant mice, motoneurons are largely eliminated and oligodendrocytes are not produced. Olig2(-/-) neuroepithelial cells in the ventral spinal cord failed to differentiate into motoneurons or oligodendrocytes and expressed an astrocyte marker, S100beta, at the time of oligodendrogenesis. Olig1 or Olig3, other family members, were expressed in the descendent cells that should have expressed Olig2. We concluded that Olig2 is an essential transcriptional regulator in motoneuron and oligodendrocyte development. Our data provide the first evidence that a single gene mutation leads to the loss of two cell types, motoneuron and oligodendrocyte.

    DOI: 10.1016/S0960-9822(02)00926-0

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  • Non-overlapping expression of Olig3 and Olig2 in the embryonic neural tube 査読

    H Takebayashi, T Ohtsuki, T Uchida, S Kawamoto, K Okubo, K Ikenaka, M Takeichi, O Chisaka, Y Nabeshima

    MECHANISMS OF DEVELOPMENT   113 ( 2 )   169 - 174   2002年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Olig family is a novel sub-family of basic helix-loop-helix transcription factors recently identified. Olig 1 and Olig2 were first reported to promote oligodendrocyte differentiation. and later Olig2 was reported to be involved in motorneuron specification as well. Olig3 was isolated as a third member of Olig family. but its precise expression pattern is poorly understood. Here, we describe detailed Olig3 expression analyses in the neural tube of embryonic mice. Olig3 was first detected in the dorsal neural tube from the hindbrain/hindbrain boundary to the spinal cord. In E11.5 spinal cord. Olig3 was transiently expressed in the lateral margin of the subventricular zone as three ventral clusters at the level of the p3, p2 and p0 domains, as well as in the dolorsal neural tube. Olig3 was co-expresed with Nkx2.2 in the lateral margin of the p3 domain. In forebrain Olig3 was expressed in the dorsal thalamus while Olig2 was complementarily expressed in the ventral thalamus with an adjacent boundary at E12.5. Olig3 is specifically and transiently expressed in different types of progenitors of embryonic central nervous system and then disappears in the course of development. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0925-4773(02)00021-7

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  • Dual origin of spinal oligodendrocyte progenitors and evidence for the cooperative role of Olig2 and Nkx2.2 in the control of oligodendrocyte differentiation. 査読

    Fu H, Qi Y, Tan M, Cai J, Takebayashi H, Nakafuku M, Richardson W, Qiu M

    Development (Cambridge, England)   129 ( 3 )   681 - 693   2002年2月

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  • Combinatorial roles of Olig2 and Neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons 査読

    R Mizuguchi, M Sugimori, H Takebayashi, H Kosako, M Nagao, S Yoshida, Y Nabeshima, K Shimamura, M Nakafuku

    NEURON   31 ( 5 )   757 - 771   2001年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Distinct classes of neurons are generated at defined times and positions during development of the nervous system. It remains elusive how specification of neuronal identity coordinates with acquisition of pan-neuronal properties. Here we show that basic helix-loop-helix (bHLH) transcription factors Olig2 and Neurogenin2 (Ngn2) play vital roles in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons. Olig2 and Ngn2 are specifically coexpressed in motoneuron progenitors. Misexpression studies in chick demonstrate the specific, combinatorial actions of Olig2 and Ngn2 in motoneuron generation. Our results further revealed crossregulatory interactions between bHLH and homeodomain transcription factors in the specification of motoneurons. We suggest that distinct classes of transcription factors collaborate to generate motoneurons in the ventral neural tube.

    DOI: 10.1016/S0896-6273(01)00413-5

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  • Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3 査読

    H Takebayashi, S Yoshida, M Sugimori, H Kosako, R Kominami, M Nakafuku, Y Nabeshima

    MECHANISMS OF DEVELOPMENT   99 ( 1-2 )   143 - 148   2000年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Basic helix-loop-helix (bHLH) transcription factors have been shown to be essential for specification of various cell types. Here, we describe a novel bHLH family consisting of three members, two of which (Olig1, Olig2) are expressed in a nervous tissue-specific manner, whereas the third, Olig3 is found mainly in non-neural tissues. Olig1 and Olig2, which recently have been implicated in oligodendrogenesis, are expressed in the region of the ventral ventricular zone of late embryonic spinal cord where oligodendrocyte progenitors appear. In the embryonic brain, the Olig2 expression domain is broader than that of Olig1 and does not overlap with an oligodendrocyte progenitor marker, CNP. Furthermore, Olig2 is expressed in most cells in the ventral half of the early embryonic spinal cord, which do not yet express an early neuronal marker TuJ1. These results indicate that Olig2 expression is not limited to the oligodendrocyte lineage but includes immature neuronal progenitors and multipotential neuron/glia progenitors as well as embryonic olfactory neurons. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S0925-4773(00)00466-4

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  • A CAG/CTG expansion in the normal population 査読

    M Nakamoto, H Takebayashi, Y Kawaguchi, S Narumiya, M Taniwaki, Y Nakamura, Y Ishikawa, Akiguchi, I, J Kimura, A Kakizuka

    NATURE GENETICS   17 ( 4 )   385 - 386   1997年12月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING CO  

    DOI: 10.1038/ng1297-385

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書籍等出版物

  • 脳神経化学

    竹林 浩秀( 担当: 分担執筆 ,  範囲: 1.脳はどのようにできているか)

    化学同人  2018年3月 

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MISC

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受賞

  • 第70回 新潟日報文化賞(学術部門)

    2017年11月  

    竹林 浩秀

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  • 2014年度 日本神経化学会優秀賞

    2014年9月  

    竹林 浩秀

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  • 平成22年度 熊本医学会奨励賞

    2011年2月  

    竹林 浩秀

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共同研究・競争的資金等の研究

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担当経験のある授業科目

  • 人体解剖学Ⅱ

    2018年
    -
    現在
    機関名:新潟大学

  • 人体の構造と機能Ⅱ(神経の構造)

    2015年
    -
    現在
    機関名:新潟大学

  • 医学研究実習

    2014年
    -
    現在
    機関名:新潟大学

  • 先端医科学研究概説

    2014年
    -
    2015年
    機関名:新潟大学

  • 発生学

    2013年
    -
    現在
    機関名:新潟大学

  • 中枢神経学

    2012年
    -
    2017年
    機関名:新潟大学

  • 人体の構造と機能II(神経の構造)

    2012年
    -
    2015年
    機関名:新潟大学

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