Updated on 2022/07/27

写真a

 
匹田 貴夫
 
Organization
Organization for Research Strategy and Development Special-Appointment Associate Professor
Position
Special-Appointment Associate Professor
Profile
大阪生まれの三重育ち。
レッツエンジョイサイエンス。
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Research Interests

  • 再生医療

  • 細胞移動

  • 生化学

  • 遺伝学

  • 包括脳ネットワーク

  • プロテオーム

  • 低分子量GTPase

  • Proteomic analysis

  • Pharmacology

  • Cell polarity

Research Areas

  • Life Science / Genetics  / C. elegansを用いた低分子量Gタンパク質の機能解析

  • Life Science / Medical biochemistry  / 血管内皮細胞の極性と炎症

  • Life Science / Pharmacology  / 血管内皮細胞障害と糖尿病合併症

  • Life Science / Neuroscience-general  / 神経細胞移動・再生医療・精神疾患原因遺伝子

Education

  • 名古屋大学大学院   医学系研究科   博士課程

    2002.4 - 2006.3

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  • Nara Institute of Science and Technology   バイオサイエンス研究科   博士課程前期

    2000.4 - 2002.3

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  • Kagawa University   農学部   生物資源学科

    1996.4 - 2000.3

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Research History

  • Okayama University   Organization for Research Promotion & Collaboration

    2021.10

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  • マックスプランク心肺研究所   ポストドクトラルフェロー

    2014.4 - 2022.1

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  • Nagoya City University   Graduate School of Medical Sciences, Department of Developmental and Regenerative Biology   Assistant Professor

    2010.4 - 2013.3

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  • Nagoya City University   Graduate School of Medical Sciences, Department of Developmental and Regenerative Biology

    2009.4 - 2010.3

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  • 名古屋大学医学部 神経情報薬理学講座   ポストドクトラルフェロー

    2006.4 - 2009.3

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Papers

  • Poor vaccine responsiveness towards third-dose mRNA vaccine of COVID-19 in Japanese older people

    Hideharu Hagiya, Takao Hikita, Tomohiro Habu, Masaki Asada, Takashi Yorifuji, Shinichi Toyooka, Fumio Otsuka, Masanori Nakayama

    Journal of Infection   2022.7

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    DOI: 10.1016/j.jinf.2022.07.007

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  • Numerical evaluation reveals the effect of branching morphology on vessel transport properties during angiogenesis Reviewed

    Fatemeh Mirzapour-Shafiyi, Yukinori Kametani, Takao Hikita, Yosuke Hasegawa, Masanori Nakayama

    PLoS Computational Biology   17 ( 6 )   e1008398   2021.6

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  • Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. Reviewed International journal

    Mengnan Li, Shin-Ya Nishio, Chie Naruse, Meghan Riddell, Sabrina Sapski, Tatsuya Katsuno, Takao Hikita, Fatemeh Mizapourshafiyi, Fiona M Smith, Leanne T Cooper, Min Goo Lee, Masahide Asano, Thomas Boettger, Marcus Krueger, Astrid Wietelmann, Johannes Graumann, Bryan W Day, Andrew W Boyd, Stefan Offermanns, Shin-Ichiro Kitajiri, Shin-Ichi Usami, Masanori Nakayama

    Nature communications   11 ( 1 )   1343 - 1343   2020.3

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    Enlarged vestibular aqueduct (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function.

    DOI: 10.1038/s41467-020-15198-9

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  • Regulation of programmed cell death ligand 1 expression by atypical protein kinase C lambda/iota in cutaneous angiosarcoma. Reviewed International journal

    Ai Kawamura, Takuji Kawamura, Meghan Riddell, Takao Hikita, Teruki Yanagi, Hiroshi Umemura, Masanori Nakayama

    Cancer science   110 ( 5 )   1780 - 1789   2019.5

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    The expression of immune checkpoint proteins such as programmed cell death protein 1 (PD-1) and its ligand (PD-L1) has been shown to correlate with patient prognosis in many malignant cancers. The expression of PD-L1 is controlled by c-Myc; however, further upstream regulation of PD-L1 expression is largely unknown. We have previously shown that atypical protein kinase C lambda/iota (aPKCλ) phosphorylates the Forkhead box protein O1 (FoxO1) transcription factor at Ser218 to suppress its DNA-binding ability, thereby regulating c-Myc expression and controlling physiologic and pathologic endothelial proliferation. The presence of phosphorylation of FoxO1 at Ser218 (pSer218 FoxO1) in cutaneous angiosarcoma (CAS) strongly correlates with poor patient prognosis. Here, we reported that patients with PD-L1+ cells in CAS lesions showed significantly worse prognosis compared to those that were PD-L1- . Expression of PD-L1 correlated with that of aPKCλ or the presence of pSer218FoxO1. Moreover, suppression of aPKCλ expression or inhibition of its activity in HUVECs or AS-M, an established human angiosarcoma cell line, resulted in decreased PD-L1 expression. Our results suggest that combined treatment with immune checkpoint inhibitors and aPKCλ inhibitors could be a novel treatment strategy for CAS patients.

    DOI: 10.1111/cas.13981

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  • aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability. Reviewed International journal

    Meghan Riddell, Akiko Nakayama, Takao Hikita, Fatemeh Mirzapourshafiyi, Takuji Kawamura, Ayesha Pasha, Mengnan Li, Mikio Masuzawa, Mario Looso, Tim Steinbacher, Klaus Ebnet, Michael Potente, Tomonori Hirose, Shigeo Ohno, Ingrid Fleming, Stefan Gattenlöhner, Phyu P Aung, Thuy Phung, Osamu Yamasaki, Teruki Yanagi, Hiroshi Umemura, Masanori Nakayama

    Nature communications   9 ( 1 )   5357 - 5357   2018.12

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    Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

    DOI: 10.1038/s41467-018-07739-0

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  • PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow. Reviewed International journal

    Hikita T, Mirzapourshafiyi F, Barbacena P, Riddell M, Pasha A, Li M, Kawamura T, Brandes RP, Hirose T, Ohno S, Gerhardt H, Matsuda M, Franco CA, Nakayama M

    EMBO reports   19 ( 9 )   2018.9

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    Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro-inflammatory, suggesting that the establishment of endothelial polarity elicits an anti-inflammatory response. However, a causative relationship between polarity and inflammatory responses has not been firmly established. Here, we find that a cell polarity protein, PAR-3, is an essential gatekeeper of GSK3β activity in response to laminar blood flow. We show that flow-induced spatial distribution of PAR-3/aPKCλ and aPKCλ/GSK3β complexes controls local GSK3β activity and thereby regulates endothelial planar polarity. The spatial information for GSK3β activation is essential for flow-dependent polarity to the flow axis, but is not necessary for flow-induced anti-inflammatory response. Our results shed light on a novel relationship between endothelial polarity and vascular homeostasis highlighting avenues for novel therapeutic strategies.

    DOI: 10.15252/embr.201745253

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  • Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell-cell Adhesion in the Postnatal Brain. Reviewed International journal

    Fujikake K, Sawada M, Hikita T, Seto Y, Kaneko N, Herranz-Pérez V, Dohi N, Homma N, Osaga S, Yanagawa Y, Akaike T, García-Verdugo JM, Hattori M, Sobue K, Sawamoto K

    The Journal of neuroscience : the official journal of the Society for Neuroscience   38 ( 19 )   4598 - 4609   2018.5

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    In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and in vivo loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell-cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB.SIGNIFICANCE STATEMENT In the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell-cell adhesion between chain-forming neuroblasts, which involves adherens junction-like structures. Our results suggest that Fyn-mediated regulation of the cell-cell adhesion of neuroblasts is critical for their detachment from chains in the postnatal brain.

    DOI: 10.1523/JNEUROSCI.1960-17.2018

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  • PlexinD1 signaling controls morphological changes and migration termination in newborn neurons. Reviewed International journal

    Masato Sawada, Nobuhiko Ohno, Mitsuyasu Kawaguchi, Shih-Hui Huang, Takao Hikita, Youmei Sakurai, Huy Bang Nguyen, Truc Quynh Thai, Yuri Ishido, Yutaka Yoshida, Hidehiko Nakagawa, Akiyoshi Uemura, Kazunobu Sawamoto

    The EMBO journal   37 ( 4 )   2018.2

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    Newborn neurons maintain a very simple, bipolar shape, while they migrate from their birthplace toward their destinations in the brain, where they differentiate into mature neurons with complex dendritic morphologies. Here, we report a mechanism by which the termination of neuronal migration is maintained in the postnatal olfactory bulb (OB). During neuronal deceleration in the OB, newborn neurons transiently extend a protrusion from the proximal part of their leading process in the resting phase, which we refer to as a filopodium-like lateral protrusion (FLP). The FLP formation is induced by PlexinD1 downregulation and local Rac1 activation, which coincide with microtubule reorganization and the pausing of somal translocation. The somal translocation of resting neurons is suppressed by microtubule polymerization within the FLP The timing of neuronal migration termination, controlled by Sema3E-PlexinD1-Rac1 signaling, influences the final positioning, dendritic patterns, and functions of the neurons in the OB These results suggest that PlexinD1 signaling controls FLP formation and the termination of neuronal migration through a precise control of microtubule dynamics.

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  • Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity Reviewed

    Daisuke Tsuboi, Keisuke Kuroda, Motoki Tanaka, Takashi Namba, Yukihiko Iizuka, Shinichiro Taya, Tomoyasu Shinoda, Takao Hikita, Shinsuke Muraoka, Michiro Iizuka, Ai Nimura, Akira Mizoguchi, Nobuyuki Shiina, Masahiro Sokabe, Hideyuki Okano, Katsuhiko Mikoshiba, Kozo Kaibuchi

    NATURE NEUROSCIENCE   18 ( 5 )   698 - +   2015.5

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    Disrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major psychiatric disorders, including schizophrenia. DISC1 has been implicated in neurodevelopment in relation to scaffolding signal complexes. Here we used proteomic analysis to screen for DISC1 interactors and identified several RNA-binding proteins, such as hematopoietic zinc finger (HZF), that act as components of RNA-transporting granules. HZF participates in the mRNA localization of inositol-1,4,5-trisphosphate receptor type 1 (ITPR1), which plays a key role in synaptic plasticity. DISC1 colocalizes with HZF and ITPR1 mRNA in hippocampal dendrites and directly associates with neuronal mRNAs, including ITPR1 mRNA. The binding potential of DISC1 for ITPR1 mRNA is facilitated by HZF. Studies of Disc1-knockout mice have revealed that DISC1 regulates the dendritic transport of Itpr1 mRNA by directly interacting with its mRNA. The DISC1-mediated mRNA regulation is involved in synaptic plasticity. We show that DISC1 binds ITPR1 mRNA with HZF, thereby regulating its dendritic transport for synaptic plasticity.

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  • Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA Reviewed

    Haruko Ota*, Takao Hikita*, Masato Sawada*, Tomoki Nishioka, Mami Matsumoto, Masayuki Komura, Akihisa Ohno, Yukiyo Kamiya, Takuya Miyamoto, Naoya Asai, Atsushi Enomoto, Masahide Takahashi, Kozo Kaibuchi, Kazuya Sobue, Kazunobu Sawamoto

    NATURE COMMUNICATIONS   5   4532   2014.7

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    Throughout life, new neurons generated in the ventricular-subventricular zone take the long journey to the olfactory bulb. The intracellular mechanisms that precisely control the neurons' migration speed, enabling their well-organized movement, remain unclear. Rho signalling is known to affect the morphology and movement of various cell types, including neurons. Here we identify Gem-interacting protein (Gmip), a RhoA-specific GTPase-activating protein, as a key factor in saltatory neuronal migration. RhoA is activated at the proximal leading process of migrating neurons, where Gmip is also localized and negatively regulates RhoA. Gmip controls the saltatory movement of neurons that regulate their migration speed and 'stop' positions in the olfactory bulb, thereby altering the neural circuitry. This study demonstrates that Gmip serves as a brake for the RhoA-mediated movement of neuronal somata, and highlights the significance of speed control in the well-organized neuronal migration and the maintenance of neuronal circuits in the postnatal brain.

    DOI: 10.1038/ncomms5532

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  • Rac1-mediated indentation of resting neurons promotes the chain migration of new neurons in the rostral migratory stream of post- natal mouse brain Reviewed

    Takao Hikita, Akihisa Ohno, Masato Sawada, Haruko Ota, Kazunobu Sawamoto

    JOURNAL OF NEUROCHEMISTRY   128 ( 6 )   790 - 797   2014.3

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    New neurons generated in the ventricular-subventricular zone in the post-natal brain travel toward the olfactory bulb by using a collective cell migration process called chain migration.' These new neurons show a saltatory movement of their soma, suggesting that each neuron cycles through periods of rest' during migration. Here, we investigated the role of the resting neurons in chain migration using post-natal mouse brain, and found that they undergo a dynamic morphological change, in which a deep indentation forms in the cell body. Inhibition of Rac1 activity resulted in less indentation of the new neurons in vivo. Live cell imaging using a Forster resonance energy transfer biosensor revealed that Rac1 was activated at the sites of contact between actively migrating and resting new neurons. On the cell surface of resting neurons, Rac1 activation coincided with the formation of the indentation. Furthermore, Rac1 knockdown prevented the indentation from forming and impaired migration along the resting neurons. These results suggest that Rac1 regulates a morphological change in the resting neurons, which allows them to serve as a migratory scaffold, and thereby non-cell-autonomously promotes chain migration.

    DOI: 10.1111/jnc.12518

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  • Proteomic analysis of Girdin-interacting proteins in migrating new neurons in the postnatal mouse brain Reviewed

    Haruko Ota, Takao Hikita, Tomoki Nishioka, Mami Matsumoto, Jun Ito, Naoya Asai, Atsushi Enomoto, Masahide Takahashi, Kozo Kaibuchi, Kazuya Sobue, Kazunobu Sawamoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   442 ( 1-2 )   16 - 21   2013.12

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    Neural stem cells continuously generate new neurons in the ventricular-subventricular zone (V-SVZ) of the postnatal and adult mammalian brain. New neurons born in the rodent V-SVZ migrate toward the olfactory bulb (OB), where they differentiate into interneurons. To reveal novel intracellular molecular mechanisms that control postnatal neuronal migration, we performed a global proteomic search for proteins interacting with Girdin, an essential protein for postnatal neuronal migration. Using GST pull-down and LC-MS/MS shotgun analysis, we identified cytoskeletal proteins, cytoskeleton-binding proteins, and signal-transduction proteins as possible participants in neuronal migration. Our results suggest that Girdin and Girdin-interacting proteins control neuronal migration by regulating actin and/or microtubule dynamics. (C) 2013 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2013.10.126

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  • Growth factors released from gelatin hydrogel microspheres increase new neurons in the adult mouse brain Reviewed

    Kanako Nakaguchi, Hideo Jinnou, Naoko Kaneko, Masato Sawada, Takao Hikita, Shinji Saitoh, Yasuhiko Tabata, Kazunobu Sawamoto

    Stem Cells International   2012   915160   2012

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    Recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to injured brain tissues and differentiate into mature neurons, suggesting that such new neurons may be able to replace neurons lost to degenerative disease or injury and improve or repair neurological deficits. Here, we tested whether delivering growth factors via gelatin hydrogel microspheres would support neurogenesis in the SVZ. Insulin-like growth factor-1 (IGF-1)-containing microspheres increased the number of new neurons in the SVZ. Hepatocyte growth factor (HGF)-containing microspheres increased the number of new neurons migrating from the SVZ towards the injured striatum in a stroke model in mouse. These results suggest that the strategy of using gelatin hydrogel microspheres to achieve the sustained release of growth factors holds promise for the clinical regeneration of damaged brain tissues from endogenous neural stem cells in the adult SVZ. © 2012 Kanako Nakaguchi et al.

    DOI: 10.1155/2012/915160

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  • Growth factors released from gelatin hydrogel microspheres increase new neurons in the adult mouse brain. Reviewed

    Nakaguchi K, Jinnou H, Kaneko N, Sawada M, Hikita T, Saitoh S, Tabata Y, Sawamoto K

    Stem cells international   2012   915160   2012

  • Girdin Is an Intrinsic Regulator of Neuroblast Chain Migration in the Rostral Migratory Stream of the Postnatal Brain Reviewed

    Yun Wang, Naoko Kaneko, Naoya Asai, Atsushi Enomoto, Mayu Isotani-Sakakibara, Takuya Kato, Masato Asai, Yoshiki Murakumo, Haruko Ota, Takao Hikita, Takashi Namba, Keisuke Kuroda, Kozo Kaibuchi, Guo-li Ming, Hongjun Song, Kazunobu Sawamoto, Masahide Takahashi

    JOURNAL OF NEUROSCIENCE   31 ( 22 )   8109 - 8122   2011.6

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    In postnatally developing and adult brains, interneurons of the olfactory bulb (OB) are continuously generated at the subventricular zone of the forebrain. The newborn neuroblasts migrate tangentially to the OB through a well defined pathway, the rostral migratory stream (RMS), where the neuroblasts undergo collective migration termed "chain migration." The cell-intrinsic regulatory mechanism of neuroblast chain migration, however, has not been uncovered. Here we show that mice lacking the actin-binding Akt substrate Girdin (a protein that interacts with Disrupted-In-Schizophrenia 1 to regulate neurogenesis in the dentate gyrus) have profound defects in neuroblast chain migration along the RMS. Analysis of two gene knock-in mice harboring Girdin mutants identified unique amino acid residues in Girdin's C-terminal domain that are responsible for the regulation of neuroblast chain migration but revealed no apparent requirement of Girdin phosphorylation by Akt. Electron microscopic analyses demonstrated the involvement of Girdin in neuroblast cell-cell interactions. These findings suggest that Girdin is an important intrinsic factor that specifically governs neuroblast chain migration along the RMS.

    DOI: 10.1523/JNEUROSCI.1130-11.2011

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  • Promotion of neuronal migration towards the injured mouse cerebral cortex using sustained release of chemoattractant from gelatin hydrogel microspheres Reviewed

    Hiroshi Masuda, Naoko Kaneko, Eisuke Kako, Takao Hikita, Yasuhiko Tabata, Kazunobu Sawamoto

    NEUROSCIENCE RESEARCH   71   E338 - E339   2011

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    DOI: 10.1016/j.neures.2011.07.1484

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  • Immunohistochemical Study of Vesicle Monoamine Transporter 2 in the Hippocampal Region of Genetic Animal Model of Schizophrenia Reviewed

    Shuji Iritani, Hirotaka Sekiguchi, Chikako Habuchi, Takao Hikita, Shinichiro Taya, Kozo Kaibuchi, Norio Ozaki

    SYNAPSE   64 ( 12 )   948 - 953   2010.12

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    Recent research in the etiology of schizophrenia revealed that there may be some neurodevelopmental failures such as neuronal network incompetence in the brain of this disease, and neurotransmitters cannot function accurately or adequately. But, it is unknown precisely what kinds of deficit in neurotransmission may be existed histopathologically. We investigated the expression of vesicle monoamine transporter 2 (VMAT2), which has a significant role in neurotransmission, in the hippocampal formation of the animal model of schizophrenia, 14-3-3epsilon hetero knockout (KO) mouse, using an immunohistochemical staining technique to clarify the neuronal abnormalities in the model animal. As a result, the expression of VMAT2 was increased significantly in the hippocampal formation of 14-3-3epsilon hetero KO mice compared to that of the wild-type littermates. In conclusion, these findings might be related the pathophysiology of this disease includes a monoaminergic transmission abnormality, based on the investigation in a genetically-modified mouse as schizophrenic model. Synapse 64:948-953, 2010. (C)2010 Wiley-Liss, Inc.

    DOI: 10.1002/syn.20846

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  • Dysfunction of dopamine release in the prefrontal cortex of dysbindin deficient sandy mice: An in vivo microdialysis study Reviewed

    Taku Nagai, Yuko Kitahara, Anna Shiraki, Takao Hikita, Shinichiro Taya, Kozo Kaibuchi, Kiyofumi Yamada

    NEUROSCIENCE LETTERS   470 ( 2 )   134 - 138   2010.2

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    Dystrobrevin binding protein-1 gene (DTNBP1), which encodes dysbindin protein, has been identified as a schizophrenia susceptibility gene. Dysbindin has been shown to contribute to the regulation of exocytosis and formation of synaptic vesicles. Although hypofrontality in schizophrenia underlies its pathophysiology, the molecular function of dysbindin in synaptic neurotransmission remains unclear. In the present study, we investigated depolarization-evoked dopamine (DA) and serotonin (5-HT) release in the prefrontal cortex (PFC) of sandy (sdy) mice, which have a deletion mutation in the gene encoding DTNBP1. In vivo microdialysis analysis revealed that extracellular DA levels in the PFC of wild-type mice were increased by 60 mM KCl stimulation, and the KCl-evoked DA release was significantly decreased in sdy mice compared with wild-type mice. Extracellular 5-HT levels in the PFC of wild-type mice were also increased by 60 mM KCl stimulation. The KCl-evoked 5-HT release did not differ between wild-type and sdy mice. There was no difference in basal levels of DA and 5-HT before the stimulation between two groups. Behavioral sensitization after repeated methamphetamine (METH) treatment was significantly reduced in sdy mice compared with wild-type mice whereas no difference was observed in METH-induced hyperlocomotion between two groups. These results suggest that dysbindin may have a role in the regulation of depolarization-evoked DA release in the PFC and in the development of behavioral sensitization induced by repeated METH treatment. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.neulet.2009.12.071

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  • Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein Reviewed

    Takao Hikita, Shinichiro Taya, Yasutaka Fujino, Setsuko Taneichi-Kuroda, Kanae Ohta, Daisuke Tsuboi, Tomoyasu Shinoda, Keisuke Kuroda, Yusuke Funahashi, Junko Uraguchi-Asaki, Ryota Hashimoto, Kozo Kaibuchi

    JOURNAL OF NEUROCHEMISTRY   110 ( 5 )   1567 - 1574   2009.9

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    Schizophrenia is a complex mental disorder with fairly high level of heritability. Dystrobrevin binding protein 1, a gene encoding dysbindin protein, is a susceptibility gene for schizophrenia that was identified by family-based association analysis. Recent studies revealed that dysbindin is involved in the exocytosis and/or formation of synaptic vesicles. However, the molecular function of dysbindin in synaptic transmission is largely unknown. To investigate the signaling pathway in which dysbindin is involved, we isolated dysbindin-interacting molecules from rat brain lysate by combining ammonium sulfate precipitation and dysbindin-affinity column chromatography, and identified dysbindin-interacting proteins by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry. Proteins involved in protein localization process, including Munc18-1, were identified as dysbindininteracting proteins. Munc18-1 was co-immunoprecipitated with dysbindin from rat brain lysate, and directly interacted with dysbindin in vitro. In primary cultured rat hippocampal neurons, a part of dysbindin was co-localized with Munc18-1 at pre-synaptic terminals. Our result suggests a role for dysbindin in synaptic vesicle exocytosis via interaction with Munc18-1.

    DOI: 10.1111/j.1471-4159.2009.06257.x

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  • Association analysis between schizophrenia and the AP-3 complex genes Reviewed

    Ryota Hashimoto, Kazutaka Ohi, Takeya Okada, Yuka Yasuda, Hidenaga Yamamori, Hiroaki Hori, Takao Hikita, Shinichiro Taya, Osamu Saitoh, Asako Kosuga, Masahiko Tatsumi, Kunitoshi Kamijima, Kozo Kaibuchi, Masatoshi Takeda, Hiroshi Kunugi

    NEUROSCIENCE RESEARCH   65 ( 1 )   113 - 115   2009.9

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    A susceptibility gene for schizophrenia, dysbindin, is a component of BLOC-1, which interacts with the adaptor protein (AP)-3 complex. As a direct interaction between dysbindin and AP-3 complex was reported, we examined a possible association between 16 SNPs in the AP3 complex genes and schizophrenia using 432 cases and 656 controls. Nominal association between rs6688 in the AP3M1 gene and schizophrenia (chi(2) = 6.33, P = 0.012, odds ratio = 0.80) was no longer positive after correction for Multiple testing (corrected P = 0.192). The present results Suggest that AP3 complex genes might not play a major role in the pathogenesis of schizophrenia ill this population. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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  • Direct interaction of Dysbindin with the AP-3 complex via its mu subunit Reviewed

    Setsuko Taneichi-Kuroda, Shinichiro Taya, Takao Hikita, Yasutaka Fujino, Kozo Kaibuchi

    NEUROCHEMISTRY INTERNATIONAL   54 ( 7 )   431 - 438   2009.6

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    Genetic factors are important in the etiology of schizophrenia. Recent studies have revealed the association between genetic variation of Dysbindin (DTNBP1) and schizophrenia. Dysbindin is one of the essential components of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). BLOC-1 physically interacts with the adaptor protein (AP)-3 complex, which is essential for vesicle or protein sorting. However, it remains largely unknown how BLOC-1 interacts with the AP-3 complex. To investigate the binding mode of BLOC-1 and the AP-3 complex, we examined the relation between Dysbindin and the AP-3 complex and found that Dysbindin formed a complex with the AP-3 complex through the direct binding to its mu subunit. Dysbindin partially co-localized with the AP-3 complex in CA1 and CA3 of mouse hippocampus, and at presynaptic terminals and axonal growth cones of cultured hippocampal neurons. Suppression of Dysbindin results in the reduction of presynaptic protein expression and glutamate release. Thus, Dysbindin appears to participate in the exocytosis or sorting of the synaptic vesicle via direct interaction with the AP-3 complex. (C) 2009 Elsevier Ltd. All rights reserved.

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  • Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia Reviewed

    Masashi Ikeda*, Takao Hikita*, Shinichiro Taya*, Junko Uraguchi-Asaki, Kazuhito Toyo-oka, Anthony Wynshaw-Boris, Hiroshi Ujike, Toshiya Inada, Keizo Takao, Tsuyoshi Miyakawa, Norio Ozaki, Kozo Kaibuchi, Nakao Iwata

    HUMAN MOLECULAR GENETICS   17 ( 20 )   3212 - 3222   2008.10

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    Schizophrenia is a complex mental disorder with a fairly high degree of heritability. Although the causes of schizophrenia remain unclear, it is now widely accepted that it is a neurodevelopmental and neurodegenerative disorder involving disconnectivity and disorder of the synapses. Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene involved in neurodevelopment, including maturation of the cerebral cortex. To identify other susceptibility genes for schizophrenia, we screened for DISC1-interacting molecules [NudE-like (NUDEL), Lissencephaly-1 (LIS1), 14-3-3epsilon (YWHAE), growth factor receptor bound protein 2 (GRB2) and Kinesin family 5A of Kinesen1 (KIF5A)], assessing a total of 25 tagging single-nucleotide polymorphisms (SNPs) in a Japanese population. We identified a YWHAE SNP (rs28365859) that showed a highly significant difference between case and control samples, with higher minor allele frequencies in controls (P(allele) = 1.01 x 10(-5) and P(genotype) = 4.08 x 10(-5) in 1429 cases and 1728 controls). Both messenger RNA transcription and protein expression of 14-3-3epsilon were also increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor alleles compared with homozygous major allele subjects. To further investigate a potential role for YWHAE in schizophrenia, we studied Ywhae(+/-) mice in which the level of 14-3-3epsilon protein is reduced to 50% of that in wild-type littermates. These mice displayed weak defects in working memory in the eight-arm radial maze and moderately enhanced anxiety-like behavior in the elevated plus-maze. Our results suggest that YWHAE is a possible susceptibility gene that functions protectively in schizophrenia.

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  • Establishment of a tissue-specific RNAi system in C-elegans Reviewed

    Hiroshi Qadota, Makiko Inoue, Takao Hikita, Mathias Koeppen, Jeffrey D. Hardin, Mutsuki Arnano, Donald G. Moerman, Kozo Kaibuchi

    GENE   400 ( 1-2 )   166 - 173   2007.10

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    In C. elegans, mosaic analysis is a powerful genetic tool for determining in which tissue or specific cells a gene of interest is required. For traditional mosaic analysis, a loss-of-function mutant and a genomic fragment that can rescue the mutant phenotype are required. Here we establish an easy and rapid mosaic system using RNAi (RNA mediated interference), using a rde-1 mutant that is resistant to RNAi. Tissue-specific expression of the wild type rde-1 cDNA in rde-1 mutants limits RNAi sensitivity to a specific tissue. We established hypodermal-and muscle-specific RNAi systems by expressing rde-1 cDNA under the control of the lin-26 and hlh-1 promoters, respectively. We confirmed tissue-specific RNAi using two assays: (1) tissue-specific knockdown of GFP expression, and (2) phenocopy of mutations in essential genes that were previously known to function in a tissue-specific manner. We also applied this system to an essential gene, ajm-1, expressed in hypodermis and gut, and show that lethality in ajm-1 mutants is due to loss of expression in hypodermal cells. Although we demonstrate tissue-specific RNAi in hypodermis and muscle, this method could be easily applied to other tissues. (c) 2007 Elsevier B.V. All rights reserved.

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  • DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2 Reviewed

    Tomoyasu Shinoda, Shinichiro Taya, Daisuke Tsuboi, Takao Hikita, Reiko Matsuzawa, Setsuko Kuroda, Akihiro Iwamatsu, Kozo Kaibuchi

    JOURNAL OF NEUROSCIENCE   27 ( 1 )   4 - 14   2007.1

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    Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3 epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.

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  • DISC1 regulates the transport of the NUDEL/LIS1/14-3-3 epsilon complex through Kinesin-1 Reviewed

    Shinichiro Taya, Tomoyasu Shinoda, Daisuke Tsuboi, Junko Asaki, Kumiko Nagai, Takao Hikita, Setsuko Kuroda, Keisuke Kuroda, Mariko Shimizu, Shinji Hirotsune, Akihiro Iwamatsu, Kozo Kaibuchi

    JOURNAL OF NEUROSCIENCE   27 ( 1 )   15 - 26   2007.1

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    Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3 epsilon. 14-3-3 epsilon is involved in the proper localization of NUDEL and LIS1 in axons. Although the functional significance of this complex in neuronal development has been reported, the transport mechanism of the complex into axons and their functions in axon formation remain essentially unknown. Here we report that Kinesin-1, a motor protein of anterograde axonal transport, was identified as a novel DISC1-interacting molecule. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3 epsilon complex through DISC1, and these molecules localized mainly at cell bodies and partially in the distal part of the axons. DISC1 partially colocalized with Kinesin family member 5A, NUDEL, LIS1, and 14-3-3 epsilon in the growth cones. The knockdown of DISC1 by RNA interference or the dominant-negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3 epsilon at the axons and axon elongation. The knockdown or the dominant-negative form of Kinesin-1 inhibited the accumulation of DISC1 at the axons and axon elongation. Furthermore, the knockdown of NUDEL or LIS1 inhibited axon elongation. Together, these results indicate that DISC1 regulates the localization of NUDEL/LIS1/14-3-3 epsilon complex into the axons as a cargo receptor for axon elongation.

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  • Regulatory machinery of UNC-33Ce-CRMP localization in neurites during neuronal development in Caenorhabditis elegans Reviewed

    D Tsuboi, T Hikita, H Qadota, M Amano, K Kaibuchi

    JOURNAL OF NEUROCHEMISTRY   95 ( 6 )   1629 - 1641   2005.12

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    In Caenorhabditis elegans, unc-33 encodes an orthologue of the vertebrate collapsin response mediator protein (CRMP) family. We previously reported that CRMP-2 accumulated in the distal part of the growing axon of vertebrate neurons and played critical roles in axon elongation. unc-33 mutants show axonal outgrowth defects in several neurons. It has been reported that UNC-33 accumulates in neurites, whereas a missense mutation causes the mislocalization of UNC-33 from neurites to cell body, which suggests that the localization of UNC-33 in neurites is important for axonal outgrowth. However, it is unclear how UNC-33 accumulates in neurites and regulates neuronal development. In this study, to understand the regulatory mechanisms of localization of UNC-33 in neurites, we screened for the mutants that were involved in the localization of UNC-33, and identified three mutants: unc-14 (RUN domain protein), unc-51 (ULK kinase) and unc-116 (kinesin heavy chain). UNC-14 is known to associate with UNC-51. UNC-116 forms a complex with KLC-2 as Kinesin-1, a microtubule-dependent motor complex. We found that UNC-33 interacted with UNC-14 and KLC-2 in vivo. These results suggest that the UNC-14/UNC-51 complex and Kinesin-1 are involved in the localization of UNC-33 in neurites.

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  • Identification of a novel Cdc42 GEF that is localized to the PAT-3-mediated adhesive structure Reviewed

    T Hikita, H Qadota, D Tsuboi, S Taya, DG Moerman, K Kaibuchi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   335 ( 1 )   139 - 145   2005.9

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    In the model organism Caenorhabditis elegans, UNG-112 is colocalized with PAT-3/beta-integrin and is a critical protein in the formation of PAT-3-mediated adhesive structure in body-wall muscle cells. However, the signaling pathway downstream of PAT-3/UNC-112 is largely unknown. To clarify the signaling pathway from PAT-3/UNC-112 to the actin cytoskeleton, we searched for and identified a novel Dbl homology/pleckstrin homology (DH/PH) domain containing protein, UIG-1 (UNC-112-interacting guanine nucleotide exchange factor-1). UIG-1 was colocalized with UNC-112 at dense bodies in body-wall muscle cells. UIG-1 showed CDC-42-specific GEF activity in vitro and induced filopodia formation in NIH 3T3 cells. Depletion of CDC-42 or PAT-3 in the developmental stage, by RNAi, prevented the formation of continuous actin filament in body-wall muscle cells. Taken together, these results suggest that UIG-1 links a PAT-3/UNC-112 complex to the CDC-42 signaling pathway during muscle formation. (c) 2005 Elsevier Inc. All rights reserved.

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MISC

  • 【神経再生の最前線】内在性神経幹細胞を用いた神経再生

    松本 真実, 匹田 貴夫, 澤本 和延

    BIO Clinica   28 ( 13 )   1228 - 1232   2013.12

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    近年、神経幹細胞は発達期のみならず成体脳においても存在し、生涯を通じて新しいニューロンやグリア細胞を産生することが明らかとなった。マウスなどの病態モデルを用いた研究により、側脳室外側壁の脳室下帯で産生されたニューロンが、正常時には嗅球へ移動する一方で、脳梗塞などの際には傷害部へ移動・成熟することが明らかになった。このような内在性神経幹細胞の神経再生能力をヒトの脳で活性化させることができれば、新たな神経再生医療へ応用できる可能性がある。(著者抄録)

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  • 実験講座 培養脳スライスを用いた新生ニューロンのライブイメージング

    藤掛 数馬, 匹田 貴夫, 祖父江 和哉, 澤本 和延

    Surgery Frontier   20 ( 3 )   333 - 337   2013.9

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    近年の研究によって、再生医療は多くの難治性疾患に対する新たな可能性を生み出した。中枢神経系においても例外ではなく、再生医療の臨床応用に期待が寄せられている。培養脳スライスを用いたライブイメージングは脳の再生医学における強力な研究手段のひとつであり、必要不可欠な手法である。本稿では、筆者らが実際に行っている培養脳スライスを用いた新生ニューロンのライブイメージングの実験手順概説と、それを用いた実験例について紹介する。(著者抄録)

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  • 脳梗塞後の修復メカニズムと細胞治療 脳修復過程における内在性神経前駆細胞の移動

    藤掛 数馬, 匹田 貴夫, 祖父江 和哉, 澤本 和延

    脳循環代謝   24 ( Suppl. )   102 - 106   2013.8

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    脳梗塞の治療は最新の研究成果をもとに治療基準が更新され、急性期死亡率の改善が認められている。しかし脳梗塞後遺症や脳血管性痴呆患者の介護は大きな社会問題となっており、ダメージを受けた脳組織そのものを再生させる再生医療が期待されている。現在筆者らは、ゼブラフィッシュ・マウス・コモンマーモセットの様々な病態モデルを用いて、脳に内在する神経幹細胞によって脳細胞が再生される過程をイメージングし、その分子・細胞機構を解明するとともに、再生を促進する技術を開発するための実験を進めている。これらの異なる動物種を用いて再生能力を比較しながら研究することにより、ヒトの神経が再生しにくい理由や、再生効率を高める方法のヒントが得られると考えている。(著者抄録)

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  • 脳卒中の再生医療に向けて

    太田 晴子, 匹田 貴夫, 祖父江 和哉, 澤本 和延

    循環器内科   68 ( 4 )   393 - 397   2010.10

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  • 【組織幹細胞のあらたな発見とその臨床応用】成体の脳組織における神経幹細胞と再生医療

    匹田 貴夫, 澤本 和延

    医学のあゆみ   231 ( 11 )   1112 - 1116   2009.12

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    幹細胞とは自己複製能と多分化能を兼ね備えた細胞である。神経系の細胞を産生する幹細胞は神経幹細胞とよばれ、脳を構成するニューロンおよびグリア細胞はすべて神経幹細胞より生みだされる。発生期においては、おもに脳室帯(ventricular zone:VZ)に存在する神経幹細胞がニューロンおよびグリア細胞を産生して脳組織を形成する。一方、成熟した個体の脳に神経幹細胞は存在しないとされていたが、近年の研究により霊長類を含む高等生物の成体脳においても神経幹細胞が存在し、ニューロンおよびグリア細胞が一生にわたり産生されていることが明らかにされた。齧歯類の成体脳では海馬歯状回および脳室下帯に神経幹細胞が存在し、あらたなニューロンを供給している。本稿では神経幹細胞について概説するとともに、脳室下帯における神経新生に焦点を当て解説する。(著者抄録)

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  • 統合失調症関連蛋白質dysbindinの新規結合パートナーのプロテオーム解析による解明(Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein)

    匹田 貴夫, 田谷 真一郎, 藤野 泰孝, 橋本 亮太, 貝淵 弘三

    日本細胞生物学会大会講演要旨集   61回   222 - 222   2009.5

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  • 新規統合失調症発症脆弱性候補因子としての14-3-3epsilonの同定

    匹田 貴夫, 池田 匡志, 田谷 真一郎, 岩田 仲生, 貝淵 弘三

    日本薬理学雑誌   133 ( 3 )   32P - 32P   2009.3

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  • 新規Dysbindin結合分子としてのAP-3複合体の同定(Identification of the AP-3 complex as a novel Dysbindin-interacting molecule)

    藤野 泰孝, 匹田 貴夫, 黒田 摂子, 田谷 真一郎, 貝淵 弘三

    神経化学   47 ( 2-3 )   228 - 228   2008.8

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  • 統合失調症脆弱性因子DISC1によるNUDEL複合体、Grb2の軸索への輸送制御

    匹田 貴夫, 田谷 真一郎, 篠田 友靖, 貝淵 弘三

    日本薬理学雑誌   130 ( 3 )   7P - 7P   2007.9

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  • 統合失調症末期海馬ニューロンにおけるDisrupted-In-Shizophrenia-1の役割(Roles of Disrupted-In-Schizophrenia-1 in the later stage of hippocampal neuron)

    坪井 大輔, 田谷 真一郎, 篠田 友靖, 匹田 貴夫, 黒田 摂子, 貝淵 弘三

    神経化学   44 ( 2-3 )   184 - 184   2005.8

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Awards

  • EMBO Short-Term Fellowships

    2015.1   The European Molecular Biology Organization  

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  • Mark A. Smith Prize

    2013.8   International Society for Neurochemistry   Rac1-mediated indentation of resting neurons, promotes the chain migration of new neurons in the rostral migratory stream of post-natal mouse brain

    Takao Hikita

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Research Projects

  • 血管と脂肪組織が形成する炎症ポジティブフィードバックループの解明

    Grant number:22K08125  2022.04 - 2025.03

    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)

    匹田 貴夫

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • ほ乳類成体脳における新生細胞の運命決定・移動・極性形成

    2011.04 - 2012.04

    二国間交流事業 フランスとの共同研究(INSERM) 

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    Grant amount:\5000000

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  • Cell adhesion mechanism of migrating new neurons

    Grant number:23700385  2011 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    HIKITA Takao

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    New neurons migrating in the rostral migratory stream of postnatal brain shows specific fashion of collective cell migration, ‘chain migration’. To clarify a molecular mechanism that control chain migration, we searched for cell-cell adhesion molecules that is expressed in new neurons, and identified two adhesion molecules. By using inhibitors, we identified signaling pathway that regulates localization of the adhesion molecules in new neurons. Furthermore, by using FRET -based biosensors, we observed an activation of Rho family small GTPases in the cell-cell contact site of new neurons. Further studies will be performed to establish a method to control migration and direction of new neurons in vivo.

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