2021/10/20 更新

写真a

ワタナベ ケイスケ
渡辺 啓介
WATANABE Keisuke
所属
教育研究院 医歯学系 医学系列 講師
医歯学総合研究科 生体機能調節医学専攻 機能再建医学 講師
職名
講師
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外部リンク

学位

  • 博士(理学) ( 2006年3月   総合研究大学院大学 )

研究キーワード

  • 軸索誘導

  • 大脳皮質

  • 細胞移動

  • 包括脳ネットワーク

  • 中隔核

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 / 発生生物学

経歴(researchmap)

  • 新潟大学大学院   医歯学総合研究科 肉眼解剖学   講師

    2015年8月 - 現在

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  • 新潟大学大学院   医歯学総合研究科 肉眼解剖学   助教

    2015年3月 - 2015年7月

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  • 新潟大学大学院   医歯学総合研究科 神経解剖学   助教

    2012年4月 - 2015年2月

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  • 熊本大学   医学薬学研究部   助教

    2007年4月 - 2012年3月

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  • 生理学研究所   研究員

    2006年4月 - 2007年3月

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  • 理学博士 (総合研究大学院大学)

    2006年3月

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経歴

  • 新潟大学   医歯学総合研究科 生体機能調節医学専攻 機能再建医学   講師

    2015年8月 - 現在

  • 新潟大学   医学部 医学科   助教

    2012年4月 - 2015年7月

  • 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   助教

    2012年4月 - 2015年7月

所属学協会

 

論文

  • 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  

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

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

    Scientific reports   8 ( 1 )   11728   2018年8月

  • 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.

    DOI: 10.1371/journal.pone.0167985

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  • Developmental origin of the clavicle, and its implications for the evolution of the neck and the paired appendages in vertebrates 査読

    Hiroshi Nagashima, Fumiaki Sugahara, Keisuke Watanabe, Masahiro Shibata, Akina Chiba, Noboru Sato

    JOURNAL OF ANATOMY   229 ( 4 )   536 - 548   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  

    In fish, the pectoral appendage is adjacent to the head, but during vertebrate evolution a long neck region emerged via caudal relocation of the pectoral appendage. The pectoral appendage is comprised of endochondral portions, such as the humerus and the scapula, and a dermal portion, such as the clavicle, that contributes to the shoulder girdle. In the search for clues to the mechanism of the caudal relocation of the pectoral appendage, the cell lineage of the rostral lateral plate mesoderm was analyzed in chickens. It was found that, despite the long neck region in chickens, the origin of the clavicle attached to the head mesoderm ranged between 1 and 14 somite levels. Because the pectoral limb bud and the endochondral pectoral appendage developed on 15-20 and 15-24 somite levels, respectively, the clavicle-forming region corresponds to the embryonic neck, which suggests that the relocation would have been executed by the expansion of the source of the clavicle. The rostral portion of the clavicle-forming region overlaps the source of the cucullaris muscle, embraces the pharyngeal arches caudally, and can be experimentally replaced with the head mesoderm to form the cucullaris muscle, which implies that the mesodermal portion could have been the head mesodermand that the clavicle would have developed at the head/trunk boundary. The link between the head mesoderm and the presumptive clavicle appears to have been the developmental constraint needed to create the evolutionarily conserved musculoskeletal connectivities characterizing the gnathostome neck. In this sense, the dermal girdle of the ganathostomes would represent the wall of the branchial chamber into which the endochondral pectoral appendage appears to have attached since its appearance in evolution.

    DOI: 10.1111/joa.12502

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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:WILEY-BLACKWELL  

    ObjectiveFocal 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.
    MethodsWe 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.
    ResultsWe 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.
    InterpretationWe found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb. Ann Neurol 2015;78:375-386

    DOI: 10.1002/ana.24444

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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.

    DOI: 10.1111/ejn.12711

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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.

    DOI: 10.1186/1471-2202-13-140

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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.

    DOI: 10.1242/dev.069997

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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.

    DOI: 10.1038/nn.3020

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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.

    DOI: 10.1242/dev.068155

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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.

    DOI: 10.1371/journal.pone.0025465

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  • Tangential migration and proliferation of intermediate progenitors of GABAergic neurons in the mouse telencephalon 査読

    Shengxi Wu, Shigeyuki Esumi, Keisuke Watanabe, Jing Chen, Kouichi C. Nakamura, Kazuhiro Nakamura, Kouhei Kometani, Nagahiro Minato, Yuchio Yanagawa, Kaori Akashi, Kenji Sakimura, Takeshi Kaneko, Nobuaki Tamamaki

    DEVELOPMENT   138 ( 12 )   2499 - 2509   2011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:COMPANY OF BIOLOGISTS LTD  

    In the embryonic neocortex, neuronal precursors are generated in the ventricular zone (VZ) and accumulate in the cortical plate. Recently, the subventricular zone (SVZ) of the embryonic neocortex was recognized as an additional neurogenic site for both principal excitatory neurons and GABAergic inhibitory neurons. To gain insight into the neurogenesis of GABAergic neurons in the SVZ, we investigated the characteristics of intermediate progenitors of GABAergic neurons (IPGNs) in mouse neocortex by immunohistochemistry, immunocytochemistry, single-cell RT-PCR and single-cell array analysis. IPGNs were identified by their expression of some neuronal and cell cycle markers. Moreover, we investigated the origins of the neocortical IPGNs by Cre-loxP fate mapping in transgenic mice and the transduction of part of the telencephalic VZ by Cre-reporter plasmids, and found them in the medial and lateral ganglionic eminence. Therefore, they must migrate tangentially within the telencephalon to reach the neocortex. Cell-lineage analysis by simple-retrovirus transduction revealed that the neocortical IPGNs self-renew and give rise to a small number of neocortical GABAergic neurons and to a large number of granule and periglomerular cells in the olfactory bulb. IPGNs are maintained in the neocortex and may act as progenitors for adult neurogenesis.

    DOI: 10.1242/dev.063032

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  • Netrin 1 Provides a Chemoattractive Cue for the Ventral Migration of GnRH Neurons in the Chick Forebrain 査読

    Shizuko Murakami, Hiroko Ohki-Hamazaki, Keisuke Watanabe, Kazuhiro Ikenaka, Katsuhiko Ono

    JOURNAL OF COMPARATIVE NEUROLOGY   518 ( 11 )   2019 - 2034   2010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:WILEY-LISS  

    Hypothalamic gonadotropin-releasing hormone (GnRH) neurons originate in the olfactory placode and migrate to the forebrain during embryonic development. We found that GnRH neurons migrated in two different modes in the chick medial telencephalon: they initially underwent axophilic migration in association with a subset of olfactory fibers in a dorsocaudal direction. This was followed by ventrally directed tangential migration to the basal forebrain. Since many of the ventrally migrating GnRH neurons did not follow distinct fiber fascicles, it is proposed that diffusible guidance molecules played a role in this migratory process. A long-range diffusible factor, netrin 1, was expressed in the lower part of the commissural plate and the subpallial septum, but not along the axophilic migratory route of GnRH neurons. Failure of ventrally directed migration of GnRH neurons and their misrouting to the dorsomedial forebrain was induced by misexpression of netrin 1 in the dorsocaudal part of the septum near the top of the commissural plate, which is where the migration of GnRH neurons changed to a ventral direction. In such cases, a subset of olfactory fibers also extended, but close contact between aberrant fibers and misrouted GnRH neurons did not exist. A coculture experiment demonstrated that netrin 1 exerts an attractive effect on migrating GnRH neurons. These results provide evidence that netrin 1 acts as chemoattractant to migrating GnRH neurons at the dorsocaudal part of the septum and has the potential to regulate the ventral migration of GnRH neurons to the ventral septum and the preoptic area. J. Comp. Neurol. 518:2019-2034, 2010. (C) 2010 Wiley-Liss, Inc.

    DOI: 10.1002/cne.22319

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  • The ratio of 'deleted in colorectal cancer' to 'uncoordinated-5A' netrin-1 receptors on the growth cone regulates mossy fibre directionality 査読

    Rieko Muramatsu, Soichiro Nakahara, Junya Ichikawa, Keisuke Watanabe, Norio Matsuki, Ryuta Koyama

    BRAIN   133 ( 1 )   60 - 75   2010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:OXFORD UNIV PRESS  

    Proper axonal targeting is fundamental to the establishment of functional neural circuits. The hippocampal mossy fibres normally project towards the CA3 region. In the hippocampi of patients with temporal lobe epilepsy and related animal models, however, mossy fibres project towards the molecular layer and produce the hyperexcitable recurrent networks. The cellular and molecular mechanisms underlying this aberrant axonal targeting, known as mossy fibre sprouting, remain unclear. Netrin-1 attracts or repels axons depending on the composition of its attraction-mediating receptor, deleted in colorectal cancer, and its repulsion-mediating receptor, uncoordinated-5, on the growth cone; but the roles of netrin-1-dependent guidance in pathological conditions are largely unknown. In this study, we examined the role of netrin-1 and its receptors in mossy fibre guidance and report that enhanced neuronal activity changes netrin-1-mediated cell targeting by the axons under hyperexcitable conditions. Netrin-1 antibody or Dcc ribonucleic acid interference attenuated mossy fibre growth towards CA3 in slice overlay assays. The axons were repelled from CA3 and ultimately innervated the molecular layer when hyperactivity was pharmacologically introduced. We first hypothesized that a reduction in netrin-1 expression in CA3 underlies the phenomenon, but found that its expression was increased. We then examined two possible activity-dependent changes in netrin-1 receptor expression: a reduction in the deleted in colorectal cancer receptor and induction of uncoordinated-5 receptor. Hyperactivity did not affect the surface expression of the deleted in colorectal cancer receptor on the growth cone, but it increased that of uncoordinated-5A, which was suppressed by blocking cyclic adenosine monophosphate signalling. In addition, Dcc knockdown did not affect hyperactivity-induced mossy fibre sprouting in the slice cultures, whereas Unc5a knockdown rescued the mistargeting. Thus, netrin-1 appears to attract mossy fibres via the deleted in colorectal cancer receptor, while it repels them via cyclic adenosine monophosphate-induced uncoordinated-5A under hyperexcitable conditions, resulting in mossy fibre sprouting.

    DOI: 10.1093/brain/awp266

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  • Parvalbumin neurons in the forebrain as revealed by parvalbumin-Cre transgenic mice 査読

    Chiyoko Tanahira, Shigeyoshi Higo, Keisuke Watanabe, Ryohei Tomioka, Satoe Ebihara, Takeshi Kaneko, Nobuaki Tamamaki

    NEUROSCIENCE RESEARCH   63 ( 3 )   213 - 223   2009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 IRELAND LTD  

    Neurons expressing the calcium-binding protein parvalbumin (PV) constitute an abundant subpopulation of GABAergic neurons in the cerebral cortex. However, PV is not unique to the GABAergic neurons of the forebrain, but is also expressed in a small number of pyramidal neurons and in a large number of thalamic neurons. In order to summarize the PV neurons in the forebrain, we employed the PV-Cre transgenic mice in the present study. In the progeny of crossbreed between PV-Cre mice and GFP-Cre reporter mice, we found that the GFP-positive neurons include many excitatory neurons in the neocortex and the thalamus as well as GABAergic neurons in the cerebral cortex and basal ganglia. All the reported PV-positive GABAergic neurons in the cerebral cortex and the basal ganglia seemed to be included in the GFP-positive cells. We found GFP-positive layer V pyramidal neurons inhabit a broader neocortical area than was previously reported. They were located in the primary somatosensory, motor, and visual areas. The somatosensory area of the neocortex contained the greatest number of PV-positive pyramidal neurons. A large number of thalamic relay neurons and virtually all the reticular thalamic neurons appeared as GFP-positive. Thalamic relay nucleus and a neocortical area for the same modality corresponded and seemed to contain a characteristic amount of PV-positive excitatory neurons. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

    DOI: 10.1016/j.neures.2008.12.007

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  • Netrin-1 Acts as a Repulsive Guidance Cue for Sensory Axonal Projections toward the Spinal Cord 査読

    Tomoyuki Masuda, Keisuke Watanabe, Chie Sakuma, Kazuhiro Ikenaka, Katsuhiko Ono, Hiroyuki Yaginuma

    JOURNAL OF NEUROSCIENCE   28 ( 41 )   10380 - 10385   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  

    During early development, the ventral spinal cord expresses chemorepulsive signals that act on dorsal root ganglion (DRG) axons to help orient them toward the dorsolateral part of the spinal cord. However, the molecular nature of this chemorepulsion is mostly unknown. We report here that netrin-1 acts as an early ventral spinal cord-derived chemorepellent for DRGaxons. In the developing mouse spinal cord, netrin-1 is expressed in the floor plate of the spinal cord, and the netrin receptor Unc5c is expressed in DRGneurons. We show that human embryonic kidney cell aggregates secreting netrin-1 repel DRG axons and that netrin-1-deficient ventral spinal cord explants lose their repulsive influence on DRG axons. In embryonic day 10 netrin-1 mutant mice, we find that DRG axons exhibit transient misorientation. Furthermore, by means of gain-of-function analyses, we show that ectopic netrin-1 in the dorsal and intermediate spinal cord prevents DRGaxons from being directed toward the dorsal spinal cord. Together, these findings suggest that netrin-1 contributes to the formation of the initial trajectories of developing DRG axons as a repulsive guidance cue.

    DOI: 10.1523/JNEUROSCI.1926-08.2008

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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.

    DOI: 10.1016/j.ydbio.2008.06.001

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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.

    DOI: 10.1016/j.ydbio.2006.02.029

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  • Dorsally derived netrin 1 provides an inhibitory cue and elaborates the 'waiting period' for primary sensory axons in the developing spinal cord 査読

    K Watanabe, N Tamamaki, T Furuta, SL Ackerman, K Ikenaka, K Ono

    DEVELOPMENT   133 ( 7 )   1379 - 1387   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:COMPANY OF BIOLOGISTS LTD  

    Dorsal root ganglion (DRG) neurons extend axons to specific targets in the gray matter of the spinal cord. During development, DRG axons grow into the dorsolateral margin of the spinal cord and projection into the dorsal mantle layer occurs after a 'waiting period' of a few days. Netrin 1 is a long-range diffusible factor expressed in the ventral midline of the developing neural tube, and has chemoattractive and chemorepulsive effects on growing axons. Netrin 1 is also expressed in the dorsal spinal cord. However, the roles of dorsally derived netrin 1 remain totally unknown. Here, we show that dorsal netrin 1 controls the correct guidance of primary sensory axons. During the waiting period, netrin 1 is transiently expressed or upregulated in the dorsal spinal cord, and the absence of netrin 1 results in the aberrant projection of sensory axons, including both cutaneous and proprioceptive afferents, into the dorsal mantle layer. Netrin 1 derived from the dorsal spinal cord, but not the floor plate, is involved in the correct projection of DRG axons. Furthermore, netrin 1 suppresses axon outgrowth from DRG in vitro. Unc5c(rcm) mutant shows abnormal invasion of DRG axons as observed in netrin 1 mutants. These results are the first direct evidence that netrin 1 in the dorsal spinal cord acts as an inhibitory cue for primary sensory axons and is a crucial signal for the formation of sensory afferent neural networks.

    DOI: 10.1242/dev.02312

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  • Localization of interleukin-18 and its receptor in somatotrophs of the bovine anterior pituitary gland 査読

    Y Nagai, T Nochi, K Watanabe, K Watanabe, H Aso, H Kitazawa, M Matsuzaki, S Ohwada, T Yamaguchi

    CELL AND TISSUE RESEARCH   322 ( 3 )   455 - 462   2005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:SPRINGER  

    A pro-inflammatory cytokine, interleukin 18 (IL-18), induces intracellular expression of IL-1 and the release of IL-6. IL-1 and IL-6 has been detected in anterior pituitary cells, suggesting that IL-18 is produced in anterior pituitary cells and may serve to aid immuno-endocrine regulation. In the present study, we addressed this hypothesis by investigating the intracellular localization of IL-18 and its receptor in bovine anterior pituitary gland. IL-18 mRNA and its protein were detected in the anterior pituitary gland by RT-PCR and Western blotting. In situ hybridization showed that IL-18 mRNA was expressed in the anterior pituitary cells. Immunohistochemistry of IL-18 and specific hormones revealed the presence of IL-18 in somatotrophs. Furthermore, the expression of GH mRNA in IL-18 immunoreactive cells was confirmed by immuno-laser microdissection. These results first demonstrated that somatotrophs produced IL-18. Subsequently, the distribution of the IL-18 receptor alpha (IL-18R alpha) was investigated in order to understand IL-18 signaling among the anterior pituitary cells. Bovine IL-18R alpha cDNA was partially sequenced and detected in the anterior pituitary gland by RT-PCR. Immunohistochemistry of IL-18R alpha, IL-18 and GH showed that IL-18R alpha was co-localized in IL-18 immunoreactive cells or somatotrophs. These data suggest that IL-18 acts on somatotrophs as an immuno-endocrine mediator through the autocrine pathway.

    DOI: 10.1007/s00441-005-0016-0

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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.

    DOI: 10.1002/dvdy.20545

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共同研究・競争的資金等の研究

  • 恐怖・不安を制御する神経回路の発生プログラムの解明

    研究課題/領域番号:19K07263  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    渡辺 啓介

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

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  • 恐怖行動に関わる中隔核形成の遺伝的プログラムの解明

    2017年 - 2019年3月

    財団法人・武田科学振興財団  医学研究奨励 

    渡辺 啓介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 恐怖反応を制御する神経回路形成の分子機構の解明

    研究課題/領域番号:15K06736  2015年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    渡辺 啓介

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    配分額:4940000円 ( 直接経費:3800000円 、 間接経費:1140000円 )

    本能行動を制御する神経回路の形成メカニズムについては明らかにされていないことが多い。本研究において、生来の恐怖行動が減弱しているDpy19L1ノックアウト(KO)マウスの神経回路構築異常の解析を行った。その結果、Dpy19L1 KOマウスにおいて、恐怖・不安行動に関わる後方中隔核の形成異常を見出した。さらに、後方中隔核ニューロンは終脳外、間脳前方端のthalamic eminenceと呼ばれる領域で産生され、前方移動を経て、中隔核に加わることがわかった。Dpy19L1は細胞移動、軸索突起伸展を制御することから、後方中隔核ニューロンの移動を制御することで後方中隔核の形成に関わることが示唆された。

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  • 大脳新皮質形成に特異的な分子機構の解明

    研究課題/領域番号:25123703  2013年 - 2014年

    文部科学省  科学研究費補助金(新学術領域研究(研究領域提案型))  新学術領域研究(研究領域提案型)

    渡辺 啓介

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

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  • 大脳皮質形成における新規移動制御分子Dpy19ファミリーの機能解析

    研究課題/領域番号:24700356  2012年 - 2014年

    文部科学省  科学研究費補助金(若手研究(B))  若手研究(B)

    渡辺 啓介

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

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  • 精神遅滞発症メカニズムの解明を目指した大脳皮質興奮性ニューロン特異的な樹状突起形成機構の解明

    2012年 - 2013年

    財団法人・武田科学振興財団  医学系研究奨励継続 

    渡辺 啓介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 精神遅滞発症メカニズムの解明を目指した大脳皮質興奮性ニューロン特異的な樹状突起形成機構の解明

    2010年 - 2012年

    財団法人・武田科学振興財団  医学系研究奨励 

    渡辺 啓介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 大脳皮質特異的な発生メカニズムの解析

    2010年

    財団法人・内藤記念科学振興財団  内藤記念特定研究助成金 

    渡辺 啓介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 発生期脊髄背側部におけるnetrin1 の時期・領域特異的な発現調節機構の解明

    研究課題/領域番号:19700297  2007年 - 2009年

    文部科学省  科学研究費補助金(若手研究(B))  若手研究(B)

    渡辺 啓介

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3640000円 ( 直接経費:3100000円 、 間接経費:540000円 )

    本研究では、マウス発生期脊髄において、軸索誘導分子netrin-1が背側部で産生される神経細胞を脊髄腹側部まで誘導することを明らかにした。さらに、線虫でnetrin-Dccシグナルとの関与が示唆されているGsg1が、発生期大脳皮質における適切な神経細胞の移動と樹状突起形成に重要な役割をもつことが示唆された。これらの結果から、発生期の神経回路網形成に重要なnetrin-1のさらなる重要性を明らかになった。

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担当経験のある授業科目(researchmap)

  • 神経解剖学・脳実習

    機関名:新潟大学

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  • 骨学実習

    機関名:新潟大学

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  • 肉眼解剖学実習

    機関名:新潟大学

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  • 人体発生学

    機関名:新潟大学

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