2024/04/23 更新

写真a

ヤノ マサト
矢野 真人
YANO Masato
所属
教育研究院 医歯学系 医学系列 准教授
医歯学総合研究科 生体機能調節医学専攻 感覚統合医学 准教授
職名
准教授
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外部リンク

学位

  • 博士(医学) ( 2005年3月   大阪大学 )

研究キーワード

  • RNAプロセッシング

  • HITS-CLIP

  • RNA結合蛋白質

  • 非コードRNA

  • 神経変性疾患

  • 分子神経生物学

  • 包括脳ネットワーク

研究分野

  • ライフサイエンス / 分子生物学

  • ライフサイエンス / 神経科学一般

  • ライフサイエンス / 病態神経科学

経歴(researchmap)

  • 慶應義塾大学   医学部生理学教室   訪問准教授

    2014年12月 - 現在

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  • 新潟大学   大学院医歯学総合研究科   准教授

    2014年12月 - 現在

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  • 慶應義塾大学   医学部   講師

    2011年10月 - 2014年11月

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  • ロックフェラー大学   ポスドク

    2006年 - 2011年

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  • 慶應義塾大学   日本学術振興会特別研究員

    2005年

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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 感覚統合医学   准教授

    2014年12月 - 現在

学歴

  • 大阪大学   大学院医学系研究科

    - 2005年3月

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  • 東京工業大学   生命理工学部

    - 1999年3月

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所属学協会

委員歴

  • 日本神経科学学会   評議員  

    2023年3月 - 現在   

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  • 日本再生医療学会   代議員  

    2022年10月 - 現在   

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  • 日本RNA学会   会計幹事  

    2015年4月 - 2019年   

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    団体区分:学協会

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論文

  • Sbp2l contributes to oligodendrocyte maturation through translational control in Tcf7l2 signaling 査読

    Masato Yugami, Yoshika Hayakawa-Yano, Takahisa Ogasawara, Kazumasa Yokoyama, Takako Furukawa, Hiroe Hara, Kentaro Hashikami, Isamu Tsuji, Hirohide Takebayashi, Shinsuke Araki, Hideyuki Okano, Masato Yano

    iScience   108451 - 108451   2023年11月

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    担当区分:最終著者, 責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.isci.2023.108451

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  • DNA damage stress-induced translocation of mutant FUS proteins into cytosolic granules and screening for translocation inhibitors 査読

    Masahiro Nogami, Osamu Sano, Keiko Adachi-Tominari, Yoshika Hayakawa-Yano, Takako Furukawa, Hidehisa Iwata, Kazuhiro Ogi, Hideyuki Okano, Masato Yano

    Frontiers in Molecular Neuroscience   15   2022年12月

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    担当区分:筆頭著者, 最終著者, 責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    Fused in sarcoma/translated in liposarcoma (FUS) is an RNA-binding protein, and its mutations are associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), through the DNA damage stress response, aberrant stress granule (SG) formation, etc. We previously reported that translocation of endogenous FUS into SGs was achieved by cotreatment with a DNA double-strand break inducer and an inhibitor of DNA-PK activity. In the present study, we investigated cytoplasmic SG formation using various fluorescent protein-tagged mutant FUS proteins in a human astrocytoma cell (U251) model. While the synergistic enhancement of the migration of fluorescent protein-tagged wild-type FUS to cytoplasmic SGs upon DNA damage induction was observed when DNA-PK activity was suppressed, the fluorescent protein-tagged FUS<sup>P525L</sup> mutant showed cytoplasmic localization. It migrated to cytoplasmic SGs upon DNA damage induction alone, and DNA-PK inhibition also showed a synergistic effect. Furthermore, analysis of 12 sites of DNA-PK–regulated phosphorylation in the N-terminal LC region of FUS revealed that hyperphosphorylation of FUS mitigated the mislocalization of FUS into cytoplasmic SGs. By using this cell model, we performed screening of a compound library to identify compounds that inhibit the migration of FUS to cytoplasmic SGs but do not affect the localization of the SG marker molecule G3BP1 to cytoplasmic SGs. Finally, we successfully identified 23 compounds that inhibit FUS-containing SG formation without changing normal SG formation.

    HighlightsCharacterization of DNA-PK-dependent FUS stress granule localization.

    A compound library was screened to identify compounds that inhibit the formation of FUS-containing stress granules.

    DOI: 10.3389/fnmol.2022.953365

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  • Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy 査読

    Nozomu Yoshioka, Masayuki Kurose, Masato Yano, Dang Minh Tran, Shujiro Okuda, Yukiko Mori-Ochiai, Masao Horie, Toshihiro Nagai, Ichizo Nishino, Shinsuke Shibata, Hirohide Takebayashi

    eLife   11   e78419   2022年8月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:eLife Sciences Publications, Ltd  

    Dystonin (DST), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. DST mutations cause different disorders, including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in DST-related diseases has been unclear. Because DST-b contains all of the DST-a-encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a Dst-b-specific mutant mouse model harboring a nonsense mutation. Dst-b mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in Dst-b mutation-induced cardiomyopathy. RNA-sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified DST-b alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by DST-b mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.

    DOI: 10.7554/elife.78419

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    その他リンク: https://cdn.elifesciences.org/articles/78419/elife-78419-v1.xml

  • Involvement of ferroptosis in human motor neuron cell death. 査読 国際誌

    Tsuyoshi Matsuo, Keiko Adachi-Tominari, Osamu Sano, Takayuki Kamei, Masahiro Nogami, Kazuhiro Ogi, Hideyuki Okano, Masato Yano

    Biochemical and biophysical research communications   566   24 - 29   2021年6月

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    担当区分:最終著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ferroptosis was recently defined as a novel type of programmed cell death depending on iron and lipid peroxidation. It is biologically different from other types of cell death such as apoptosis. While the involvement of ferroptosis in cancer, patient and animal model have been intensely studied, ferroptosis in human motor neuron model is still clearly unknown. Here we carefully assessed ferroptosis using human iPS cell-derived motor neuron (hiMNs). We found that almost all hiMNs died by the treatment of glutathione peroxidase 4 (GPX4) inhibitors. Importantly, the cell death was rescued by one antioxidant, vitamin E acetate, iron chelators and lipid peroxidase inhibitors with high dynamic ranges. Finally, these data clearly indicated that ferroptosis constitutively occurs in hiMNs, suggesting the possibility that it might play a biologically and pathologically important roles in motor neuron death such as motor neuron disease (MND)/Amyotrophic lateral sclerosis (ALS).

    DOI: 10.1016/j.bbrc.2021.05.095

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  • Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN. 査読 国際誌

    Masahiro Nogami, Mitsuru Ishikawa, Atsushi Doi, Osamu Sano, Takefumi Sone, Tetsuya Akiyama, Masashi Aoki, Atsushi Nakanishi, Kazuhiro Ogi, Masato Yano, Hideyuki Okano

    Neurobiology of disease   155   105364 - 105364   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)  

    Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of amyotrophic lateral sclerosis (ALS). Mutated FUS causes accumulation of DNA damage and cytosolic stress granule (SG) formation, thereby motor neuron (MN) death. However, key molecular aetiology remains unclear. Here, we applied a novel platform technology, iBRN, "Non- biased" Bayesian gene regulatory network analysis based on induced pluripotent stem cell (iPSC)-derived cell model, to elucidate the molecular aetiology using transcriptome of iPSC-derived MNs harboring FUSH517D. iBRN revealed "hub molecules", which strongly influenced transcriptome network, such as miR-125b-5p-TIMELESS axis and PRKDC for the molecular aetiology. Next, we confirmed miR-125b-5p-TIMELESS axis in FUSH517D MNs such that miR-125b-5p regulated several DNA repair-related genes including TIMELESS. In addition, we validated both introduction of miR-125b-5p and knocking down of TIMELESS caused DNA damage in the cell culture model. Furthermore, PRKDC was strongly associated with FUS mis-localization into SGs by DNA damage under impaired DNA-PK activity. Collectively, our iBRN strategy provides the first compelling evidence to elucidate molecular aetiology in neurodegenerative diseases.

    DOI: 10.1016/j.nbd.2021.105364

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  • DGCR8-dependent efficient pri-miRNA processing of human pri-miR-9-2 査読

    Masahiro Nogami, Kazumasa Miyamoto, Yoshika Hayakawa-Yano, Atsushi Nakanishi, Masato Yano, Hideyuki Okano

    Journal of Biological Chemistry   296   100409 - 100409   2021年

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    担当区分:責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.jbc.2021.100409

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  • Analysis of the nucleocytoplasmic shuttling RNA-binding protein HNRNPU using optimized HITS-CLIP method 査読 国際誌

    Yugami M, Okano H, Nakanishi A, Yano M

    PLos One   15 ( 4 )   e0231450   2020年4月

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    担当区分:最終著者, 責任著者  

    DOI: 10.1371/journal.pone.0231450

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  • An RNA Switch of a Large Exon of Ninein Is Regulated by the Neural Stem Cell Specific-RNA Binding Protein, Qki5. 査読

    Hayakawa-Yano Y, Yano M

    International journal of molecular sciences   20 ( 5 )   2019年2月

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    担当区分:最終著者, 責任著者  

    DOI: 10.3390/ijms20051010

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

    Hayakawa-Yano Y, Suyama S, Nogami M, Yugami M, Koya I, Zhou L, Abe M, Sakimura K, Takebayashi H, Nakanishi A, Okano H, Yano M

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

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    担当区分:最終著者, 責任著者   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.

    DOI: 10.1101/gad.300822.117

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  • RNA regulation went wrong in neurodevelopmental disorders: The example of Msi/Elavl RNA binding proteins 査読

    Masato Yano, Yoshika Hayakawa-Yano, Hideyuki Okano

    INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE   55   124 - 130   2016年12月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    RNA regulation participates in many aspects of brain development. There is substantial evidence that RNA dysregulation is critical in the pathogenesis of neurodevelopmental disorders, neurological diseases, and cancer. Several gene families encode RNA-binding proteins (RNABPs) that bind directly to RNA and orchestrate the post-transcriptional regulation of gene expression, including pre-mRNA splicing, stability, and poly(A) site usage. Among neural RNABPs, the Elavl and Msi families are the focus of neuronal development research owing to their hierarchical expression pattern: Msi1 is expressed in neural progenitor/stem cells, Elavl2 is expressed in early neuronal progenitors to mature neurons, and Elavl3/4 expression begins slightly later, during cortical neuron development. Traditional biochemical analyses provide mechanistic insight into RNA regulation by these RNABPs, and Drosophila and mouse genetic studies support a relationship between these RNABPs and several neurodevelopmental disorders. In addition, a recent cohort analysis of the human genome shows that genetic mutations and SNPs in these RNABPs are associated with various neurological disorders. Newly emerged technologies assess transcriptome-wide RNA-protein interactions in vivo. These technologies, combined with classical genetics methods, provide new insight into Elavl and Msi, not only with respect to their neurodevelopmental functions, but also their roles in several diseases. We review recent discoveries related to the two RNABP families in brain development and disease. (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.ijdevneu.2016.01.002

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  • Musashi mediates translational repression of the Drosophila hypoxia inducible factor 査読

    Agustina P. Bertolin, Maximiliano J. Katz, Masato Yano, Berta Pozzi, Julieta M. Acevedo, Dalmiro Blanco-Obregon, Lautaro Gandara, Eleonora Sorianello, Hiroshi Kanda, Hideyuki Okano, Anabella Srebrow, Pablo Wappner

    NUCLEIC ACIDS RESEARCH   44 ( 16 )   7555 - 7567   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)   出版者・発行元:OXFORD UNIV PRESS  

    Adaptation to hypoxia depends on a conserved alpha/beta heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose alpha-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3' UTR of the HIF alpha transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIF alpha repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1 alpha transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available.

    DOI: 10.1093/nar/gkw372

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  • Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma 査読

    Raymond G. Fox, Nikki K. Lytle, Dawn V. Jaquish, Frederick D. Park, Takahiro Ito, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. Kopp, Marcie Kritzik, Jason K. Sicklick, Maike Sander, Paul M. Grandgenett, Michael A. Hollingsworth, Shinsuke Shibata, Donald Pizzo, Mark A. Valasek, Roman Sasik, Miriam Scadeng, Hideyuki Okano, Youngsoo Kim, A. Robert MacLeod, Andrew M. Lowy, Tannishtha Reya

    NATURE   534 ( 7607 )   407 - +   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:NATURE PUBLISHING GROUP  

    Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance1. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

    DOI: 10.1038/nature17988

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  • Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells. 査読 国際誌

    Ichiyanagi N, Fujimori K, Yano M, Ishihara-Fujisaki C, Sone T, Akiyama T, Okada Y, Akamatsu W, Matsumoto T, Ishikawa M, Nishimoto Y, Ishihara Y, Sakuma T, Yamamoto T, Tsuiji H, Suzuki N, Warita H, Aoki M, Okano H

    Stem cell reports   6 ( 4 )   496 - 510   2016年4月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.stemcr.2016.02.011

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  • Acute reduction of neuronal RNA binding Elavl2 protein and Gap43 mRNA in mouse hippocampus after kainic acid treatment 査読

    Takafumi Ohtsuka, Masato Yano, Hideyuki Okano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   466 ( 1 )   46 - 51   2015年10月

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    担当区分:責任著者   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  

    Activity-dependent gene regulation in neurons has been hypothesized to be under transcriptional control and to include dramatic increases in immediate early genes (IEGs) after neuronal activity. In addition, several reports have focused on post-transcriptional regulation, which could be mediated by neuronal post-transcriptional regulators, including RNA binding proteins (RNABPs). One such protein family is the neuronal Elavls (nElavls; Elavl2, Elavl3, and Elavl4), whose members are widely expressed in peripheral and central nervous system. Previous reports showed that Elavl3 and 4 are up-regulated following repeated stimulation such as during cocaine administration, a seizure, or a spatial discrimination task. In this study, we focused on Elavl2, a candidate gene for schizophrenia and studied its role in neuronal activity. First we found that Elavl2 has a cell-type specific expression pattern that is highly expressed in hippocampal CA3 pyramidal neurons and hilar interneurons using Elavl2 specific antibody. Second, unexpectedly, we discovered that the Elavl2 protein level in the hippocampus was acutely downregulated for 3 h after a kainic acid (KA)-induced seizure in the hippocampal CA3 region. In addition, level of Gap43 mRNA, a target mRNA of Elavl2 is decreased 12 h after KA treatment, thus suggesting the involvement of Elavl2 in activity-dependent RNA regulation. (C) 2015 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2015.08.103

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  • RNA-binding protein research with transcriptome-wide technologies in neural development 査読

    Masato Yano, Takafumi Ohtsuka, Hideyuki Okano

    CELL AND TISSUE RESEARCH   359 ( 1 )   135 - 144   2015年1月

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    担当区分:責任著者   記述言語:英語   出版者・発行元:SPRINGER  

    An increasing number of studies have demonstrated that neural RNA-binding proteins (nRNABPs) participate in several steps of neural development through post-transcriptional regulation of their RNA targets (Grabowski Curr Opin Genet Dev 21:388-394, 2011). Classical genetics and in vitro biochemical approaches have identified several important RNA targets of nRNABPs linked to cell-fate decision and neuronal functions. In recent years, new technologies, such as unbiased in vivo protein-RNA interaction approaches, high-throughput sequencing-cross-linked immunoprecipitation (HITS-CLIP), microarrays, RNAseq and others, have been developed. The use of these with genetics has succeeded in defining a dynamic range of RNA targets of RNABPs at the transcriptome-wide level. This new platform also provides the mechanistic insights into a specific biological function of nRNABPs. This review highlights the discoveries and challenges of the interplay between the nRNABPs and their biological functions in neural development.

    DOI: 10.1007/s00441-014-1923-8

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  • Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain 査読

    Donny D. Licatalosi, Masato Yano, John J. Fak, Aldo Mele, Sarah E. Grabinski, Chaolin Zhang, Robert B. Darnell

    GENES & DEVELOPMENT   26 ( 14 )   1626 - 1642   2012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:COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

    Two polypyrimidine tract RNA-binding proteins (PTBs), one near-ubiquitously expressed (Ptbp1) and another highly tissue-restricted (Ptbp2), regulate RNA in interrelated but incompletely understood ways. Ptbp1, a splicing regulator, is replaced in the brain and differentiated neuronal cell lines by Ptbp2. To define the roles of Ptbp2 in the nervous system, we generated two independent Ptbp2-null strains, unexpectedly revealing that Ptbp2 is expressed in neuronal progenitors and is essential for postnatal survival. A HITS-CLIP (high-throughput sequencing cross-linking immunoprecipitation)-generated map of reproducible Ptbp2-RNA interactions in the developing mouse neocortex, combined with results from splicing-sensitive microarrays, demonstrated that the major action of Ptbp2 is to inhibit adult-specific alternative exons by binding pyrimidine-rich sequences upstream of and/or within them. These regulated exons are present in mRNAs encoding proteins associated with control of cell fate, proliferation, and the actin cytoskeleton, suggesting a role for Ptbp2 in neurogenesis. Indeed, neuronal progenitors in the Ptbp2-null brain exhibited an aberrant polarity and were associated with regions of premature neurogenesis and reduced progenitor pools. Thus, Ptbp2 inhibition of a discrete set of adult neuronal exons underlies early brain development prior to neuronal differentiation and is essential for postnatal survival.

    DOI: 10.1101/gad.191338.112

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  • Nova2 Regulates Neuronal Migration through an RNA Switch in Disabled-1 Signaling 査読

    Masato Yano, Yoshika Hayakawa-Yano, Aldo Mele, Robert B. Darnell

    NEURON   66 ( 6 )   848 - 858   2010年6月

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    担当区分:筆頭著者   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  

    Neuronal migration leads to a highly organized laminar structure in the mammalian brain, and its misregulation causes lissencephaly and behavioral and cognitive defects. Reelin signaling, which is mediated in part by a key adaptor, disabled-1 (Dab1), plays a critical but incompletely understood role in this process. We found that the neuron-specific RNA-binding protein Nova2 regulates neuronal migration in late-generated cortical and Purkinje neurons. An unbiased HITS-CLIP and exon junction array search for Nova-dependent reelin-pathway RNAs at E14.5 revealed only one candidate-an alternatively spliced isoform of Dab1 (Dab1.7bc). In utero electroporation demonstrated that Dab1.7bc was sufficient to induce neuronal migration defects in wild-type mice and exacerbate defects when Dab1 levels were reduced, whereas Dab1 overexpression mitigates defects in Nova2 null mice. Thus, Nova2 regulates an RNA switch controlling the ability of Dab1 to mediate neuronal responsiveness to reelin signaling and neuronal migration, suggesting new links between splicing regulation, brain disease, and development.

    DOI: 10.1016/j.neuron.2010.05.007

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  • Involvement of Hu and heterogeneous nuclear ribonucleoprotein K in neuronal differentiation through p21 mRNA post-transcriptional regulation 査読

    M Yano, HJ Okano, H Okano

    JOURNAL OF BIOLOGICAL CHEMISTRY   280 ( 13 )   12690 - 12699   2005年4月

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    担当区分:筆頭著者   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 BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The Hu family is a group of neuronal RNA-binding proteins required for neuronal differentiation in the developing nervous system. Previously, Hu proteins have been shown to enhance the stabilization and/or translation of target mRNAs, such as p21 ( CIP1), by binding to AU-rich elements in untranslated regions ( UTRs). In this study, we show that Hu induces p21 expression, cell cycle arrest, and neuronal differentiation in mouse neuroblastoma N1E-115 cells. p21 expression is also up-regulated during Me2SO- induced differentiation in N1E-115 cells and is controlled by post-transcriptional mechanisms through its 3'-UTR. To investigate the molecular mechanisms of Hu functions, we used a proteomics strategy to isolate Hu-interacting proteins and identified heterogeneous nuclear ribonucleoprotein (hnRNP) K. hnRNP K also specifically binds to CU-rich sequences in p21 mRNA 3'-UTR and represses its translation in both nonneuronal and neuronal cells. Further, using RNA interference experiments, we show that the Hu-p21 pathway contributes to the regulation of neurite outgrowth and proliferation in N1E-115 cells, and this pathway is antagonized by hnRNP K. Our results suggest a model in which the mutually antagonistic action of two RNA-binding proteins, Hu and hnRNP K, control the timing of the switch from proliferation to neuronal differentiation through the post-transcriptional regulation of p21 mRNA.

    DOI: 10.1074/jbc.M411119200

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  • The RNA-binding protein HuD regulates neuronal cell identity and maturation 査読

    W Akamatsu, H Fujihara, T Mitsuhashi, M Yano, S Shibata, Y Hayakawa, HJ Okano, S Sakakibara, H Takano, T Takano, T Takahashi, T Noda, H Okano

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   102 ( 12 )   4625 - 4630   2005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:NATL ACAD SCIENCES  

    Neural Hu proteins (HuB/C/D) are RNA-binding proteins that have been shown to induce neuronal differentiation activity when overexpressed in immature neural progenitor cells or undifferentiated neuronal tumors. Newly generated HuD-deficient mice exhibited a transient impaired-cranial-nerve-development phenotype at an early embryonic stage. Adult HuD-deficient mice exhibited an abnormal hind-limb reflex and poor rotarod performance. Analysis of neurosphere formation revealed that the number and self-renewal capacity of the neural stem/progenitor cells were increased in HuD-deficient mice. HuD-deficient primary neurospheres also generated a smaller number of neurons. Cohort analysis of the cellular proliferative activity by using BrdUrd and iododeoxuridine labeling revealed that the number of differentiating quiescent cells in the embryonic cerebral wall was decreased. Long-term administration of BrdUrd revealed that the number of slowly dividing stem cells in the adult subventricular zone was increased in the HuD-deficient mice. Taken together, the results suggest that HuD is required at multiple points during neuronal development, including negative regulation of proliferative activity and neuronal cell-fate acquisition of neural stem/progenitor cells.

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  • Attenuated cerebellar phenotypes in Inpp4a truncation mutants with preserved phosphatase activity. 査読 国際誌

    Dang Minh Tran, Nozomu Yoshioka, Norihisa Bizen, Yukiko Mori-Ochiai, Masato Yano, Shogo Yanai, Junya Hasegawa, Satoshi Miyashita, Mikio Hoshino, Junko Sasaki, Takehiko Sasaki, Hirohide Takebayashi

    Disease models & mechanisms   2023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)  

    Phosphoinositides (PIPs) act as intracellular signaling molecules that regulate various cellular processes. Abnormalities in PIP metabolism cause various pathological conditions, including neurodegenerative diseases, cancer, and immune disorders. Several neurological diseases with diverse phenotypes, such as ataxia with cerebellar atrophy or intellectual disability without brain malformation, are caused by mutations in INPP4A, which encodes a phosphoinositide phosphatase. This study examined two strains of Inpp4a mutant mice with distinct cerebellar phenotypes: the first Inpp4aΔEx1,2 mutant exhibited striatal degeneration without cerebellar atrophy, and the other Inpp4aΔEx23 mutant exhibited a severe striatal phenotype with cerebellar atrophy. Both strains exhibited reduced expressions of Inpp4a mutant proteins in the cerebellum. N-terminal truncated Inpp4a proteins were expressed from Inpp4aΔEx1,2 allele by alternative translation initiation and had phosphatase activity for PI(3,4)P2, whereas the Inpp4a mutant protein encoded by Inpp4aΔEx23 completely lacked phosphatase activity. The diverse phenotypes observed in Inpp4a-related neurological diseases could be due to the varying protein expression levels and retained phosphatase activity in different Inpp4a variants. These findings provide insights into the role of Inpp4a mutations in disease pathogenesis and may help to develop personalized therapy.

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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 )   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.

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  • Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs. 査読 国際誌

    Kazunari Onodera, Daisuke Shimojo, Yasuharu Ishihara, Masato Yano, Fuyuki Miya, Haruhiko Banno, Naoko Kuzumaki, Takuji Ito, Rina Okada, Bruno de Araújo Herculano, Manabu Ohyama, Mari Yoshida, Tatsuhiko Tsunoda, Masahisa Katsuno, Manabu Doyu, Gen Sobue, Hideyuki Okano, Yohei Okada

    Molecular brain   13 ( 1 )   18 - 18   2020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)  

    Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients' pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9e438::Venus, and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.

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  • Elavl3 regulates neuronal polarity through the alternative splicing of an embryo-specific exon in AnkyrinG 査読

    Yuki Ogawa, Junji Yamaguchi, Masato Yano, Yasuo Uchiyama, Hirotaka James Okano

    Neuroscience Research   135   13 - 20   2018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:Elsevier Ireland Ltd  

    Alternative splicing of RNAs diversifies the functionalities of proteins, and it is optimized for each cell type and each developmental stage. nElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Recent studies revealed that Elavl3 knockout (Elavl3−/−) mice completely lost the expression of nElavl proteins in the Purkinje cells and exhibited cerebellar dysfunction. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3−/− mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions. We revealed that exon 34 of AnkyrinG was normally included in immature neurons and was mostly excluded in mature neurons
    however, it was included in the cerebella of Elavl3−/− mice even in adulthood. In the Purkinje cells of adult Elavl3−/− mice, the length of the AnkyrinG-positive region shortened and somatic organelles leaked into the axons. These results suggested that exon 34 of AnkyrinG is an embryonic-stage-preferential exon that should be excluded from mature neurons and that Elavl3 regulates neuronal polarity through alternative splicing of this exon.

    DOI: 10.1016/j.neures.2018.03.008

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  • Analysis of induced pluripotent stem cells carrying 22q11.2 deletion. 査読 国際誌

    M Toyoshima, W Akamatsu, Y Okada, T Ohnishi, S Balan, Y Hisano, Y Iwayama, T Toyota, T Matsumoto, N Itasaka, S Sugiyama, M Tanaka, M Yano, B Dean, H Okano, T Yoshikawa

    Translational psychiatry   6 ( 11 )   e934   2016年11月

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    記述言語:英語  

    Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8, a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al., 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP, a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers (IL1B and IL6) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia.

    DOI: 10.1038/tp.2016.206

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  • Alternative Role of HuD Splicing Variants in Neuronal Differentiation 査読

    Satoru Hayashi, Masato Yano, Mana Igarashi, Hirotaka James Okano, Hideyuki Okano

    JOURNAL OF NEUROSCIENCE RESEARCH   93 ( 3 )   399 - 409   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:WILEY-BLACKWELL  

    HuD is a neuronal RNA-binding protein that plays an important role in neuronal differentiation of the nervous system. HuD has been reported to have three RNA recognition motifs (RRMs) and three splice variants (SVs) that differ in their amino acid sequences between RRM2 and RRM3. This study investigates whether these SVs have specific roles in neuronal differentiation. In primary neural epithelial cells under differentiating conditions, HuD splice variant 1 (HuD-sv1), which is a general form, and HuD-sv2 were expressed at all tested times, whereas HuD-sv4 was transiently expressed at the beginning of differentiation, indicating that HuD-sv4 might play a role compared different from that of HuD-sv1. Indeed, HuD-sv4 did not promote neuronal differentiation in epithelial cells, whereas HuD-sv1 did promote neuronal differentiation. HuD-sv4 overexpression showed less neurite-inducing activity than HuD-sv1 in mouse neuroblastoma N1E-115 cells; however, HuD-sv4 showed stronger growth-arresting activity. HuD-sv1 was localized only in the cytoplasm, whereas HuD-sv4 was localized in both the cytoplasm and the nuclei. The Hu protein has been reported to be involved in translation and alternative splicing in the cytoplasm and nuclei, respectively. Consistent with this observation, HuD-sv1 showed translational activity on p21, which plays a role in growth arrest and neuronal differentiation, whereas HuD-sv4 did not. By contrast, HuD-sv4 showed stronger pre-mRNA splicing activity than did HuD-sv1 on Clasp2, which participates in cell division. Therefore, HuD SVs might play a role in controlling the timing of proliferation/differentiation switching by controlling the translation and alternative splicing of target genes. (c) 2014 Wiley Periodicals, Inc.

    DOI: 10.1002/jnr.23496

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  • Characterization of the RNA-binding protein Musashi1 in zebrafish 査読

    Shinsuke Shibata, Masahiko Umei, Hironori Kawahara, Masato Yano, Shinji Makino, Hideyuki Okano

    BRAIN RESEARCH   1462   162 - 173   2012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:ELSEVIER SCIENCE BV  

    Musashi (Msi) is an evolutionarily conserved gene family of RNA-binding proteins (RBPs) that is preferentially expressed in the nervous system. The first member of the Msi family was identified in Drosophila. Drosophila Msi plays an important role in regulating asymmetric cell division of the sensory organ precursor cells. The mammalian orthologs, including human and mouse Musashi1 (Msi1), are neural RBPs that are strongly expressed in fetal and adult neural stem/progenitor cells (NS/PCs). Mammalian Msi1 contributes to self renewal of NS/PCs through translational regulation of several target mRNAs. In this study, the zebrafish Msi ortholog zMsi1 was identified and characterized. The normal spatial and temporal expression profiles for both protein and mRNA were determined. A series of splice variants were detected. Overall, zMsi1 was strongly expressed in neural tissue in early stages of development and exhibited similarity to mammalian Msi1 expression patterns. To reveal the in vivo function of zMsi1, morpholinos against Msi1 were introduced into one-cell stage zebrafish embryos. Knock down of zmsi1 frequently resulted in aberrant formation of the Central Nervous System (CNS). These results suggest that Msi1 plays roles in CNS development in vertebrates.
    This article is part of a Special Issue entitled "RNA-Binding Proteins". (c) 2012 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.brainres.2012.01.068

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  • [Roles of RNA binding proteins in neural development]. 査読

    Yano M, Okano HJ, Okano H

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   51 ( 16 Suppl )   2603 - 2608   2006年12月

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    記述言語:日本語   出版者・発行元:共立出版  

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  • Sox21 is a repressor of neuronal differentiation and is antagonized by YB-1 査読

    H Ohba, T Chiyoda, E Endo, M Yano, Y Hayakawa, M Sakaguchi, RB Darnell, HJ Okano, H Okano

    NEUROSCIENCE LETTERS   358 ( 3 )   157 - 160   2004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:ELSEVIER SCI IRELAND LTD  

    Sox21, a high-mobility group box transcription factor, is expressed throughout the immature neural stem/progenitor population in ventricular zone but not in the cortical plate in embryonic mouse brain and its expression is restricted to the subventricular zone in the adult brain. In undifferentiated PC 12 cells, endogenous Sox21 expression is detected but its expression ceases during the nerve growth factor (NGF)-induced neuronal differentiation. Overexpression of Sox21 results in a substantial repression of NGF-induced neurite outgrowth in PC12 cells. Further, we biochemically identified a Sox21-associating protein, Y-box binding protein I which not only binds to Sox21 but also partially restores NGF-induced neurite outgrowth of PC12 cells inhibited by Sox21. These results suggest that Sox21 is a repressor of neuronal differentiation in the developing nervous system. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2004.01.026

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  • 12(S)-hydroxyeicosatetraenoic acid induces cAMP production via increasing intracellular calcium concentration 査読

    G Hasegawa, S Kumagai, M Yano, YG Wang, Y Kobayashi, Y Saito

    FEBS LETTERS   554 ( 1-2 )   127 - 132   2003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  

    We have found that a 12-lipoxygenase metabolite of arachidonic acid, 12(S)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE), induces CAMP production in human normal fibroblast TIG-1 cells. This phenomenon was not observed in other cells tested including human embryonic kidney HEK293 cells. We have speculated that this specific response might be influenced by the kinds of isoform of adenylyl cyclase (AC) present in cells. We found that TIG-1 cells specifically expressed type VIII AC. As type VIII AC is known to be activated by an increase of calcium concentration, we determined the change of intracellular Ca2+ concentration after the addition of 12-HETE. It was elevated not only in TIG-1 cells, but also HEK293 cells, which did not respond to 12-HETE to produce CAMP. The addition of a calcium ionophore elevated the concentration of intracellular CAMP in TIG-1 cells, but it was without effect in HEK293 cells. To show that the expression of this particular isoform of AC is responsible for the positive response to 12-HETE, we transfected this AC isoform into HEK293 cells. The type VIII AC-transfected cells, in contrast to the mock-transfected ones, became very responsive to 12HETE to produce CAMP. Taken all together the data would strongly suggest that 12-HETE specifically activates type VIII AC via increasing intracellular Ca2+ concentration. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/S0014-5793(03)01128-1

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書籍等出版物

  • カンデル神経科学 第2版

    矢野真人, 岡野栄之( 担当: 共訳 ,  範囲: (2章 遺伝子と行動))

    メディカル・サイエンス・インターナショナル  2022年9月  ( ISBN:9784815730550

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    総ページ数:xlviii, 1653p   記述言語:日本語

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  • カンデル神経科学

    矢野真人, 岡野栄之( 担当: 共訳 ,  範囲: 3章 遺伝子と行動)

    株式会社 メディカル・サイエンス・インターナショナル  2014年 

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  • わかる実験医学シリーズ 転写がわかる 基本転写から発生,再生,先端医療まで 半田 宏/編

    矢野真人, 岡野栄之( 担当: 共著 ,  範囲: 転写制御による神経系の分化)

    実験医学  2004年 

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MISC

  • FUS蛋白質の細胞質顆粒移行の分子機序とその阻害低分子化合物の同定

    矢野真人, 矢野(早川)佳芳

    月刊メディカル・サイエンス・ダイジェスト (MSD)   ( 49 )   494 - 495   2023年8月

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  • RNA結合蛋白質解析の利と美—柔軟かつ堅牢性の高い脳の組織、細胞機能を包括的に理解する— 招待

    矢野真人

    神経化学   61 ( 1 )   1 - 6   2022年6月

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  • 【白血病学(下)-最新の基礎、臨床研究-】 白血病の基礎研究と臨床研究の動向 造血幹細胞と白血病幹細胞研究の動向 幹細胞と癌における細胞運命決定因子Musashiの役割

    矢野 真人, 岡野 栄之

    日本臨床   74 ( 増刊10 白血病学(下) )   503 - 507   2016年12月

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    記述言語:日本語   出版者・発行元:(株)日本臨床社  

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  • ncRNA研究をはじめよう 9.RNP解析 1):CLIP―CLIP技術の進化と今後の展開

    矢野真人, 矢野佳芳

    実験医学   33 ( 20 )   3419 - 3423   2015年12月

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    記述言語:日本語  

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  • 疾患由来iPS細胞を用いた家族性筋萎縮性側索硬化症の病態解析

    一柳直希, 藤崎央子, 矢野真人, 岡田洋平, 赤松和土, 赤松和土, 割田仁, 青木正志, 岡野栄之

    再生医療   14   2015年

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  • HITS-CLIP法; トランスクリプトームワイド 蛋白質-RNA相互作用のin vivoフットプリンティング

    矢野真人, 矢野佳芳

    日本RNA学会HP   2014年12月

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  • RNA疾患―最新の病態解析から治療法展望まで―脳内における蛋白質‐RNA相互作用の検出とその応用

    大塚貴文, 矢野真人, 岡野栄之

    月刊メディカル・サイエンス・ダイジェスト   40 ( 7 )   326 - 329   2014年6月

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    記述言語:日本語  

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  • 幹細胞制御の分子基盤【幹細胞制御とRNAネットワーク】

    矢野真人, 岡野栄之

    細胞   44 ( 9 )   381 - 384   2012年8月

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    記述言語:日本語   出版者・発行元:ニューサイエンス社  

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  • RNAの解析〈RNA解析の新技術〉HITS‐CLIP法を用いた選択的スプライシングとmiRNAの制御マップ解析

    矢野真人

    臨床検査   55 ( 9 )   865 - 871   2011年9月

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    記述言語:日本語   出版者・発行元:医学書院  

    DOI: 10.11477/mf.1542102724

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  • クローズアップ実験法 Series210 HITS‐CLIP法:タンパク質‐RNA相互作用のゲノムワイドマッピング

    矢野真人, 矢野(早川)佳芳, DARNELL Robert B

    実験医学   29 ( 1 )   105 - 114   2011年1月

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    記述言語:日本語  

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  • A role of neuronal RNA binding protein Hu and NF45/NF90 in the nervous system

    Mana Igarashi, Masato Yano, James Hirotaka Okano, Hideyuki Okano

    NEUROSCIENCE RESEARCH   65   S90 - S90   2009年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    DOI: 10.1016/j.neures.2009.09.368

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  • ROLES OF RNA BINDING PROTEIN Hu IN DEVELOPING AND MATURE NEURONS

    Hirotaka James Okano, Kyoko Kakumoto, Masato Yano, Robert B. Darnell, Hideyuki Okano

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   343 - 343   2009年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:SPRINGER TOKYO  

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  • A role of neuronal RNA-binding protein Hu and NF45/90 in the nervous system

    Mania Igarashi, Masato Yano, Hirotaka J. Okano, Hideyuki Okano

    NEUROSCIENCE RESEARCH   61   S153 - S153   2008年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    Web of Science

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  • Altered participation in neural differentiation by HuD splice variants

    Satoru Hayashi, Masato Yano, Mana Igarashi, Hiroyuki Miyoshi, Hirotaka James Okano, Hideyuki Okano

    NEUROSCIENCE RESEARCH   61   S229 - S229   2008年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    Web of Science

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  • A role of neuronal RNA binding protein Hu and NF45/90 in the nervous system

    Mana Igarashi, Masato Yano, Satoru Hayashi, Hirotaka J. Okano, Hideyuki Okano

    NEUROSCIENCE RESEARCH   55   S145 - S145   2006年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

    Web of Science

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  • 神経特異的RNA結合蛋白質Huによる神経分化制御機構の解析

    矢野真人, 赤松和土, 五十嵐真奈, 林哲, 深見伸一, 岡野ジェイムス洋尚, 岡野尚之

    RNAミーティング   7th   2005年

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  • 神経特異的RNA結合蛋白質Huの機能解析

    岡野J洋尚, 赤松和土, 矢野真人, 早川佳芳, DARNELL R, 岡野栄之

    日本神経科学大会プログラム・抄録集   24th   2001年

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講演・口頭発表等

  • 蛋白質-RNA相互作用マッピングによる新しいRNA制御モデル解明とRNA制御オリゴの同定 招待

    矢野真人

    第42回日本分子生物学会 ワークショップ "RNA結合蛋白質解析の成せる用と美"  2019年12月 

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  • RNA結合蛋白質による選択的スプライシング制御からみた神経発生機構 招待

    矢野真人

    第6回JCRベーシックリサーチカンファレンス  2019年10月 

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  • 神経系におけるHITS-CLIP解析に基づいた新しいRNA制御機構の解明とその応用の可能性 招待

    矢野真人

    第27回東京医科歯科大学・システム発生・再生医学分野セミナー  2019年10月 

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  • 蛋白質-RNA相互作用マッピングは、新しいRNA制御モデルとRNA制御オリゴの同定を可能にする 招待

    矢野真人

    第18回日本再生医療学会シンポジウム「RNA技術と幹細胞研究の最前線  2019年3月 

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    会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • 中枢神経系の細胞アイデンティティーを創出する RNA 結合蛋白質の解析 招待

    矢野真人

    武田薬品工業SILエキスパートシンポジウム”RNA-Binding Proteins in Neuroscience”  2018年7月 

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    会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • Cell-type specific RNA-binding proteins in the developing central nervous system” 招待

    矢野真人

    第41回日本神経科学大会シンポジウム RNA制御から理解する神経発生と疾患  2018年7月 

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    会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • Alternative splicing in neural stem cells 招待

    矢野真人, 矢野佳芳, 岡野栄之

    第39回日本分子生物学会 RNA結合蛋白質による細胞運命制御  2016年11月 

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    会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • 神経発生・疾患とRNA結合蛋白質 招待

    矢野真人

    第46回新潟神経学夏期セミナー RNAと神経疾患  2016年7月 

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  • 高解像度RNA制御を介した神経系細胞機能の解析 招待

    矢野真人

    大分大学テニュアトラックセミナー  2015年3月 

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  • Transcriptome wide mapping of Msi1-RNA interaction in neural stem cell 招待

    矢野真人, 岡野栄之

    第37回分子生物学会年会シンポジウムMolecular Biology of Non-coding RNAs and its Application  2014年11月 

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  • RNA 結合蛋白質 Musashi による幹細胞機能の転写後レベルでの調節機構 招待

    岡野栄之, 矢野真人

    第37回日本神経科学大会 シンポジウム  2014年9月 

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受賞

  • 宇宙兄弟ALSプロジェクトせりか基金賞

    2019年12月  

    矢野真人

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  • 三四会奨励賞

    2014年   慶應義塾大学  

    矢野真人

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  • 第55回ノーベル賞受賞者会議(リンダウ会議)文部科学省選抜派遣者

    2005年6月  

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共同研究・競争的資金等の研究

  • 新規非ドメイン型ハブ分子と低分子化合物を用いた非膜オルガネラ間-遷移機構

    研究課題/領域番号:22H05589

    2022年6月 - 2024年3月

    制度名:科学研究費助成事業 学術変革領域研究(A)

    研究種目:学術変革領域研究(A)

    提供機関:日本学術振興会

    矢野 真人

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    配分額:9360000円 ( 直接経費:7200000円 、 間接経費:2160000円 )

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  • グリア細胞におけるPKM制御と神経細胞へのエネルギー供給の意義の解明

    研究課題/領域番号:22K06879

    2022年4月 - 2025年3月

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    矢野 佳芳, 矢野 真人

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • ALS運動ニューロンの脆弱性回避の分子機構

    研究課題/領域番号:20H00485

    2020年4月 - 2024年3月

    制度名:科学研究費助成事業 基盤研究(A)

    研究種目:基盤研究(A)

    提供機関:日本学術振興会

    岡野 栄之, 矢野 真人

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    配分額:44850000円 ( 直接経費:34500000円 、 間接経費:10350000円 )

    遅発性神経変性疾患である筋萎縮性側索硬化症ALSは、表現型の出現までに、原因となる遺伝性変異などを内在しながらも長期に渡り細胞が生存、機能するため、何らかの細胞機能の脆弱性回避の分子システムの存在が示唆されている。そこで本研究は、iPS細胞を用いたin vitroのALS細胞モデルを用い、運動ニューロンの蛋白質凝集、神経突起の退縮、細胞死に至る細胞機能の脆弱性回避の分子基盤解明を目的とする。本研究計画で、我々はiBRN (“non-biased" Bayesian gene regulatory network analysis based on induced pluripotent stem cell (iPSC)-derived cell model)と名付けたiPS細胞由来神経細胞を用いたベイジアンネットワーク解析手法を用いて、家族性筋萎縮性側索硬化症(ALS)の分子病態に内在するトランスクリプトーム情報(RNA発現情報)に対して強い影響力を示すハブ遺伝子群の探索を行った。具体的には、健常者および家族性ALS患者の中でもFUS遺伝子(H517D)に変異を持つiPS細胞由来運動ニューロンの前駆細胞、分化成熟段階を含む60種類のトランスクリプトーム情報を基に、iBRN解析を実施した。その結果、病態に対するトランスクリプトーム情報に対し、強い影響力を示す3つのハブ候補遺伝子として、PRKDC、miR-125b-5p、TIMELESSを同定した。さらに、培養細胞をモデルとした検証実験によって、PRKDCの活性が、ALSの原因遺伝子であるFUS蛋白質の異常局在に関わる事、さらに、miR-125b-5pおよびTIMELESSは、直接標的とした分子経路を示し、神経細胞変性のトリガーとなりうる分子病因であるDNA損傷を引き起こす事を実証した(Nogami et al. Neuobiol. Dis 2021)。

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  • 神経変性疾患におけるエニグマティックRNA群の操作と治療応用

    2020年3月 - 2021年9月

    制度名:COCKPI-Tプロジェクト

    提供機関:武田薬品工業

    矢野真人

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    担当区分:研究代表者 

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  • 希突起膠細胞分化におけるRNA代謝-脂質代謝フィードバックループ制御機構

    研究課題/領域番号:19K07345

    2019年4月 - 2022年3月

    制度名:科学研究費助成事業 基盤研究(C)

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    矢野 佳芳, 矢野 真人

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    我々は、希突起膠細胞(OLs)の分化段階および神経系での様々な細胞種ごとのトランスクリプトーム情報を元にpSI解析を行い、OLs特異的かつ分化段階で一過性に発現する新規RNA結合蛋白質としてRochsを同定した。本研究では、Rochsの機能解析を行い、RochsがOLsにおいて脂質代謝を制御し、髄鞘の形成を制御する分子であることを同定した。さらに、Rochsは脂質代謝やOLs分化において重要な制御因子のmRNAに直接結合することが明らかになり、Rochsはその制御分子の発現調節を介して脂質代謝やOLsの成熟を正に制御する分子であることが示唆された。

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  • 脊髄運動ニューロン固有のRNA制御プログラムとALS病態の関連

    2019年 - 2022年

    提供機関:文部科学省: 科学研究費補助金(基盤研究(B))

    矢野真人

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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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  • オーファンCLIPed-ncRNA作動エレメントの神経系における意義の解明

    2017年 - 2018年

    制度名:科学研究費補助金(新学術領域研究(研究領域提案型))

    提供機関:文部科学省

    矢野 真人

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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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  • Elavl2による脳内翻訳制御機構の解析

    2016年 - 2018年

    制度名:科学研究費補助金(基盤研究 (C))

    提供機関:文部科学省

    矢野 真人

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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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  • 遺伝学およびマルチオミクス戦略による神経疾患関連新規RNA結合蛋白質の探索と機能解析

    2015年4月 - 2018年3月

    制度名:2nd SIL湘南インキュベーションラボプロジェクト

    提供機関:武田薬品工業

    矢野真人

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    担当区分:研究代表者 

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  • Musashi1ーRNA相互作用ゲノムマッピング

    研究課題/領域番号:24700333

    2012年 - 2013年

    制度名:科学研究費補助金(若手研究(B))

    研究種目:若手研究(B)

    提供機関:文部科学省

    矢野 真人

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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 )

    in vivo蛋白質-RNA相互作用検出法、HITS-CLIPにより、神経幹細胞に強く発現するRNA結合蛋白質Musashi1(Msi1)の胎生期マウス脳におけるMsi1-RNA相互作用のゲノムマッピングを行った。その結果、生体内におけるMsi1のRNA結合部位をゲノムワイド1塩基解像度で同定することに成功した。このMsi1-RNA相互作用ゲノムマップを用いる事で、新規のMsi1標的RNA遺伝子群を同定し、これまでの解析で明らかとなっていたMsi1のRNA制御に加え、新たに新規のMsi1の機能の発見を導く事ができた。

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その他研究活動

  • Editorial Board: Frontiers in Molecular Neuroscience

    2020年6月

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