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清水 健史シミズ タケシ

所属部署医学研究科脳神経生理学分野
職名講師
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Last Updated :2020/06/02

研究者基本情報

基本情報

    科研費研究者番号:60398237

学歴

  • 2000年04月 - 2003年03月, 総合研究大学院大学, 生命科学研究科
  • 1998年04月 - 2000年03月, 大阪大学, 基礎工学研究科 システム人間系
  • 1994年04月 - 1998年03月, 大阪大学, 基礎工学部

学位

  • 博士 (理学)

所属学協会

  • 日本生理学会
  • 日本神経化学会
  • 日本神経科学学会

経歴

  •   2017年08月 - 現在, 名古屋市立大学, 医学研究科 脳神経生理学, 講師
  •   2012年04月 - 2017年07月, 生理学研究所, 分子神経生理研究部門, 助教
  •   2010年04月 - 2012年03月, National University of Singapore, Mechanobiology Institute, postdoctoral fellow
  •   2008年02月 - 2010年03月, 理化学研究所 発生・再生科学総合研究センター, 体軸形成研究チーム, 研究員
  •   2003年04月 - 2008年01月, 熊本大学 発生医学研究所, 転写制御分野, ポスドク

研究活動情報

研究分野

  • ライフサイエンス, 医療薬学, 脳神経生理学
  • ライフサイエンス, 生理学, 脳神経生理学
  • ライフサイエンス, 神経科学一般

研究キーワード

    GSK3β, 神経前駆細胞, β-catenin, 分化, 細胞分裂, 増殖, 神経分化, オリゴデンドロサイト, Wnt, グリア細胞, 未分化性維持, 神経幹細胞, 細胞増殖, ミエリン, 幹細胞, メカノバイオロジー

論文

  • Mechanical regulation of oligodendrocyte morphology and maturation by the mechanosensor p130Cas, Shimizu T, Osanai Y, Tanaka KF, Thai TQ, Abe M, Natsume R, Sakimura K, Ikenaka K, Journal of Neurochemistry, 150, 158 - 172,   2019年, 査読有り
  • Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability., Kazuo Kunisawa, Takeshi Shimizu, Itaru Kushima, Branko Aleksic, Daisuke Mori, Yasuyuki Osanai, Kenta Kobayashi, Anna M Taylor, Manzoor A Bhat, Akiko Hayashi, Hiroko Baba, Norio Ozaki, Kazuhiro Ikenaka, Journal of neurochemistry, 147, (3) 395 - 408,   2018年11月, 査読有り, Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.
  • Length of myelin internodes of individual oligodendrocytes is controlled by microenvironment influenced by normal and input-deprived axonal activities in sensory deprived mouse models, Osanai Y, Shimizu T, Mori T, Hatanaka N, Kimori Y, Kobayashi K, Koyama S, Yoshimura Y, Nambu A, Ikenaka K, GLIA, 66, 2514 - 2525,   2018年, 査読有り
  • YAP Functions as a Mechanotransducer in Oligodendrocyte Morphogenesis and Maturation, Takeshi Shimizu, Yasuyuki Osanai, Kenji F. Tanaka, Manabu Abe, Rie Natsume, Kenji Sakimura, Kazuhiro Ikenaka, GLIA, 65, (2) 360 - 374,   2017年02月, 査読有り, Oligodendrocytes (OLs) are myelinating cells of the central nervous system. Recent studies have shown that mechanical factors influence various cell properties. Mechanical stimuli can be transduced into intracellular biochemical signals through mechanosensors and intracellular mechanotransducers, such as YAP. However, the molecular mechanisms underlying mechanical regulation of OLs by YAP remain unknown. We found that OL morphology and interactions between OLs and neuronal axons were affected by knocking down YAP. Mechanical stretching of OL precursor cells induced nuclear YAP accumulation and assembly of focal adhesion, key platforms for mechanotransduction. Shear stress decreased the number of OL processes, whereas a dominant-negative form of YAP suppressed these effects. To investigate the roles of YAP in postnatal OLs in vivo, we constructed a novel YAP knock-in mouse and found that in vivo overexpression of YAP widely affected OL maturation. These results indicate that YAP regulates OL morphology and maturation in response to mechanical factors.
  • Rabies virus-mediated oligodendrocyte labeling reveals a single oligodendrocyte myelinates axons from distinct brain regions, Osanai Y, Shimizu T, Mori T, Yoshimura Y, Hatanaka N, Nambu A, Kimori Y, Koyama S, Kobayashi K, Ikenaka K, GLIA, 65, 93 - 105,   2017年, 査読有り
  • Microglia-Induced Activation of Noncanonical Wnt Signaling Aggravates Neurodegeneration in Demyelinating Disorders, Takeshi Shimizu, Ron Smits, Kazuhiro Ikenaka, MOLECULAR AND CELLULAR BIOLOGY, 36, (21) 2728 - 2741,   2016年11月, 査読有り, Oligodendrocytes are myelinating cells of the central nervous system. Multiple sclerosis (MS) is a demyelinating disease characterized by both myelin loss and neuronal degeneration. However, the molecular mechanisms underlying neuronal degeneration in demyelinating disorders are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) demyelinating-mouse model of MS, inflammatory microglia produce cytokines, including interleukin-1 beta (IL-1 beta). Since microglia and noncanonical Wnt signaling components in neurons, such as the coreceptor Ror2, were observed in the spinal cords of mice with EAE (EAE mice), we postulated that the interplay between activated microglia and spinal neurons under EAE conditions is mediated through noncanonical Wnt signaling. EAE treatment upregulated in vivo expression of noncanonical Wnt signaling components in spinal neurons through microglial activation. In accordance with the neuronal degeneration detected in the EAE spinal cord in vivo, coculture of spinal neurons with microglia or the application of recombinant IL-1 beta upregulated noncanonical Wnt signaling and induced neuron death, which was suppressed by the inhibition of the Wnt-Ror2 pathway. Ectopic noncanonical Wnt signaling aggravated the demyelinating pathology in another MS mouse model due to Wnt5a-induced neurodegeneration. The linkage between activated microglia and neuronal Wnt-Ror2 signaling may provide a candidate target for therapeutic approaches to demyelinating disorders.
  • Dual Inhibition of Src and GSK3 Maintains Mouse Embryonic Stem Cells, Whose Differentiation is Mechanically Regulated by Src Signaling, Takeshi Shimizu, Jun Ueda, Jolene Caifeng Ho, Katsuhiko Iwasaki, Lorenz Poellinger, Ichiro Harada, Yasuhiro Sawada, STEM CELLS, 30, (7) 1394 - 1404,   2012年07月, 査読有り, Recent studies reveal that the mechanical environment influences the behavior and function of various types of cells, including stem cells. However, signaling pathways involved in the mechanical regulation of stem cell properties remain largely unknown. Using polyacrylamide gels with varying Young's moduli as substrates, we demonstrate that mouse embryonic stem cells (mESCs) are induced to differentiate on substrates with defined elasticity, involving the Src-ShcA-MAP kinase pathway. While the dual inhibition of mitogen-activated protein (MAP) kinase and glycogen synthase kinase 3 (GSK3), termed "2i," was reported to sustain the pluripotency of mESCs, we find it to be substrate elasticity dependent. In contrast, Src inhibition in addition to 2i allows mESCs to retain their pluripotency independent of substrate elasticity. The alter-native dual inhibition of Src and GSK3 ("alternative 2i") retains the pluripotency and self-renewal of mESCs in vitro and is instrumental in efficiently deriving mESCs from preimplantation mouse embryos. In addition, the transplantation of mESCs, maintained under the alternative 2i condition, to immunodeficient mice leads to the formation of teratomas that include differentiation into three germ layers. Furthermore, mESCs established with alternative 2i contributed to chimeric mice production and transmitted to the germline. These results reveal a role for Src-ShcA-MAP kinase signaling in the mechanical regulation of mESC properties and indicate that alternative 2i is a versatile tool for the maintenance of mESCs in serum-free conditions as well as for the derivation of mESCs. STEM CELLS 2012;30:1394-1404
  • Zinc finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain, Takeshi Shimizu, Masato Nakazawa, Shuichi Kani, Young-Ki Bae, Takashi Shimizu, Ryoichiro Kageyama, Masahiko Hibi, DEVELOPMENT, 137, (11) 1875 - 1885,   2010年06月, 査読有り, Precise control of neuronal differentiation is necessary for generation of a variety of neurons in the forebrain. However, little is known about transcriptional cascades, which initiate forebrain neurogenesis. Here we show that zinc finger genes Fezf1 and Fezf2, which encode transcriptional repressors, are expressed in the early neural stem (progenitor) cells and control neurogenesis in mouse dorsal telencephalon. Fezf1-and Fezf2-deficient forebrains display upregulation of Hes5 and downregulation of neurogenin 2, which is known to be negatively regulated by Hes5. We show that FEZF1 and FEZF2 bind to and directly repress the promoter activity of Hes5. In Fezf1-and Fezf2-deficient telencephalon, the differentiation of neural stem cells into early-born cortical neurons and intermediate progenitors is impaired. Loss of Hes5 suppresses neurogenesis defects in Fezf1-and Fezf2-deficient telencephalon. Our findings reveal that Fezf1 and Fezf2 control differentiation of neural stem cells by repressing Hes5 and, in turn, by derepressing neurogenin 2 in the forebrain.
  • Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jk complex to promote proliferation and suppress differentiation of neural precursor cells, Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T, Molecular and Cellular Biology, 24, 7427 - 7441,   2008年, 査読有り
  • Wnt signaling controls the timing of oligodendrocyte development in the spinal cord, T Shimizu, T Kagawa, T Wada, Y Muroyama, S Takada, K Ikenaka, DEVELOPMENTAL BIOLOGY, 282, (2) 397 - 410,   2005年06月, 査読有り, During spinal cord development, oligodendrocytes are generated from a restricted region of the ventral ventricular zone and then spread out into the entire spinal cord. These events are controlled by graded inductive and repressive signals derived from a local organizing center. Sonic hedgehog was identified as an essential ventral factor for oligodendrocyte lineage specification, whereas the dorsal cue was less clear. In this study, Writ proteins were identified as the dorsal factors that directly inhibit oligodendrocyte development. Writ signaling through a canonical beta-catenin pathway prevents its differentiation from progenitor to an immature state. Addition of rmFz-8/Fc, a Writ antagonist, increased the number of immature oligodendrocytes in the spinal cord explant culture, demonstrating that endogenous Writ signaling controls oligodendrocyte development. (c) 2005 Elsevier Inc. All rights reserved.

書籍等出版物

  • 神経系の分化、形成、再生, 田賀哲也, 鹿川哲史, 清水健史, 福田信治, 分子生物学イラストレイテッド 改訂第3版 269-275

講演・口頭発表等

  • Mechanical control of oligodendrocyte morphogenesis and maturation by mechanosensors, 清水健史, 長内康幸, 田中謙二, 阿部学, 夏目里恵, 﨑村建司, 飛田秀樹, 池中一裕, 日本生理学会 一般口演,   2018年03月28日
  • Roles of oligodendrocyte-neuron interactions in myelination, 清水健史, 長内康幸, 池中一裕, 日本神経化学会 シンポジウム,   2017年09月08日, 招待あり
  • Microglia-induced activation of non-canonical Wnt signaling aggravates neurodegeneration in demyelinating disorders, Takashi Shimizu, Ron Smits, Kazuhiro Ikenaka, APSN, 14th Meeting of the Asian-Pacific Society for Neurochemistry,   2016年

競争的資金

  • メカニカルストレスの生理的機能の解析, 日本学術振興会 科学研究費助成事業, 挑戦的萌芽研究,   2016年04月 - 2018年03月

教育活動情報

担当経験のある科目

  • 生理学, 名古屋市立大学


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