研究者詳細 - 篠田　友靖

神経幹細胞による「他力」活用査読有り

篠田友靖, 川上巧, 宮田卓樹

生化学 90 巻 ( 6 ) 頁： 820 - 824 2018年12月

Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics. 査読有り

Jin M, Pomp O, Shinoda T, Toba S, Torisawa T, Furuta K, Oiwa K, Yasunaga T, Kitagawa D, Matsumura S, Miyata T, Tan TT, Reversade B, Hirotsune S

Scientific reports 7 巻頁： 39902 2017年1月

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

Human mutations in KATNB1 (p80) cause severe congenital cortical malformations, which encompass the clinical features of both microcephaly and lissencephaly. Although p80 plays critical roles during brain development, the underlying mechanisms remain predominately unknown. Here, we demonstrate that p80 regulates microtubule (MT) remodeling in combination with NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein. We show that p80 shuttles between the nucleus and spindle pole in synchrony with the cell cycle. Interestingly, this striking feature is shared with NuMA. Importantly, p80 is essential for aster formation and maintenance in vitro. siRNA-mediated depletion of p80 and/or NuMA induced abnormal mitotic phenotypes in cultured mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in the mouse embryonic brain. Importantly, these results were confirmed in p80-mutant harboring patient-derived induced pluripotent stem cells and brain organoids. Taken together, our findings provide valuable insights into the pathogenesis of severe microlissencephaly, in which p80 and NuMA delineate a common pathway for neurogenesis and neuronal migration via MT organization at the centrosome/spindle pole.

DOI： 10.1038/srep39902

Synergistic action of nectins and cadherins generates the mosaic cellular pattern of the olfactory epithelium. 査読有り

Katsunuma S, Honda H, Shinoda T, Ishimoto Y, Miyata T, Kiyonari H, Abe T, Nibu K, Takai Y, Togashi H

The Journal of cell biology 212 巻 ( 5 ) 頁： 561 - 75 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Cell Biology

In the olfactory epithelium (OE), olfactory cells (OCs) and supporting cells (SCs), which express different cadherins, are arranged in a characteristic mosaic pattern in which OCs are enclosed by SCs. However, the mechanism underlying this cellular patterning is unclear. Here, we show that the cellular pattern of the OE is established by cellular rearrangements during development. In the OE, OCs express nectin-2 and N-cadherin, and SCs express nectin-2, nectin-3, E-cadherin, and N-cadherin. Heterophilic trans-interaction between nectin-2 on OCs and nectin-3 on SCs preferentially recruits cadherin via a-catenin to heterotypic junctions, and the differential distributions of cadherins between junctions promote cellular intercalations, resulting in the formation of the mosaic pattern. These observations are confirmed by model cell systems, and various cellular patterns are generated by the combinatorial expression of nectins and cadherins. Collectively, the synergistic action of nectins and cadherins generates mosaic pattern, which cannot be achieved by a single mechanism.

DOI： 10.1083/jcb.201509020

Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. 査読有り

Tsuboi D, Kuroda K, Tanaka M, Namba T, Iizuka Y, Taya S, Shinoda T, Hikita T, Muraoka S, Iizuka M, Nimura A, Mizoguchi A, Shiina N, Sokabe M, Okano H, Mikoshiba K, Kaibuchi K

Nature neuroscience 18 巻 ( 5 ) 頁： 698 - 707 2015年5月

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 Neuroscience

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.

DOI： 10.1038/nn.3984

Dysbindin-1, a schizophrenia-related molecule, is involved in the regulation of neuronal dendritic development.

Ito H, Morishita R, Shinoda T, Iwamoto I, Sudo K, Okamoto K, Nagata K

Molecular psychiatry 15 巻 ( 10 ) 頁： 969 2010年10月

統合失調症の発症脆弱因子のプロテオミクス的解析

田谷真一郎, 坪井大輔, 篠田友靖, 貝淵弘三

日本プロテオーム学会大会要旨集 2007 巻 ( 0 ) 頁： 53 - 53 2007年

記述言語：日本語出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）

統合失調症は世界人口の約１%で発病がみられる重篤な精神疾患である。統合失調症患者を対象にした遺伝学的解析から、複数の統合失調症脆弱性因子の変異が発症に密接に関与することが示唆されているが、発症の分子機構は不明である。スコットランドの統合失調症多発家系の遺伝学的解析より、第１染色体と第１１染色体の相互転座部位に位置する遺伝子としてDISC1が報告された。相互転座の保因者ではDISC1の発現レベルが低下していると考えられている。
　我々はDISC1の機能解析をするために、DISC1結合蛋白質の探索を試みた。アフィニティーカラムクロマトグラフィー法により、ラット脳の抽出液からDISC1結合蛋白質を得た。それらを質量分析により解析した結果、100種以上のDISC1結合蛋白質候補を同定した。新規の分子としてKinesin-1、14-3-3ε、Grb2、既知の分子としてNUDEL、LIS1などの複数のDISC1結合蛋白質を同定した。Kinesin-1は微小菅モーターであり、軸索先端へ分子や小胞の輸送を制御している。NUDEL、LIS1、14-3-3εは複合体を形成し神経細胞の移動を制御することが報告されている。Grb2 は神経栄養因子などのシグナル伝達経路でアダプター分子として機能する。我々は、DISC1がKinesin-1とNUDEL複合体またはGrb2を連結することを見出した。ラットの海馬初代培養神経細胞において、DISC1、Kinesin-1、NUDEL複合体、Grb2は、軸索先端部位で共局在していた。DISC1の発現を抑制した神経細胞では、軸索伸長の阻害が確認でき、NUDEL複合体やGrb2の軸索先端への局在化が阻害されていた。また、NUDELやGrb2がそれぞれ軸索伸長に必要であることを見出した。我々の結果は、DISC1が“積み荷”となるNUDEL複合体とGrb2をKinesin-1に連結させる“積み荷受容体”として機能することで、“積み荷”の軸索先端への局在化に関与していることを示唆している。DISC1の発現量が低下した場合、“積み荷”の正しい場所への輸送が不十分になり、神経細胞の発達に障害が生じると予想される。さらに、DISC1結合蛋白質候補の中から、DISC1により輸送を制御される分子の同定を試みる予定である。

DOI： 10.14889/jhupo.2007.0.53.0

CiNii Research

Inhibition of leukemia-associated RhoGEF (LARG) activity by collapsin response mediator protein-2 (CRMP-2) 査読有り

Taya, S; Shinoda, T; Nagai, K; Iwamatsu, A; Matsuura, Y; Kaibuchi, K

MOLECULAR BIOLOGY OF THE CELL 13 巻頁： 53A - 53A 2002年11月

Analyzing the effect of cell rearrangement on Delta-Notch pattern formation

Oguma, T; Takigawa-Imamura, H; Shinoda, T; Ogura, S; Uemura, A; Miyata, T; Maini, PK; Miura, T

PHYSICAL REVIEW E 107 巻 ( 6 ) 頁： 064404 2023年6月

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

The Delta-Notch system plays a vital role in many areas of biology and typically forms a salt and pepper pattern in which cells strongly expressing Delta and cells strongly expressing Notch are alternately aligned via lateral inhibition. In this study, we consider cell rearrangement events, such as cell mixing and proliferation, that alter the spatial structure itself and affect the pattern dynamics. We model cell rearrangement events by a Poisson process and analyze the model while preserving the discrete properties of the spatial structure. We investigate the effects of the intermittent perturbations arising from these cell rearrangement events on the discrete spatial structure itself in the context of pattern formation and by using an analytical approach, coupled with numerical simulation. We find that the homogeneous expression pattern is stabilized if the frequency of cell rearrangement events is sufficiently large. We analytically obtain the balanced frequencies of the cell rearrangement events where the decrease of the pattern amplitude, as a result of cell rearrangement, is balanced by the increase in amplitude due to the Delta-Notch interaction dynamics. Our framework, while applied here to the specific case of the Delta-Notch system, is applicable more widely to other pattern formation mechanisms.

DOI： 10.1103/PhysRevE.107.064404

Dorsal-to-Ventral Cortical Expansion Is Physically Primed by Ventral Streaming of Early Embryonic Preplate Neurons 国際誌

その他リンク： http://harvest.aps.org/v2/journals/articles/10.1103/PhysRevE.107.064404/fulltext

Two-photon microscopic observation of cell-production dynamics in the developing mammalian neocortex in utero. 査読有り

Kawasoe R, Shinoda T, Hattori Y, Nakagawa M, Pham TQ, Tanaka Y, Sagou K, Saito K, Katsuki S, Kotani T, Sano A, Fujimori T, Miyata T

Development, Growth and Differentiation 62 巻 ( 2 ) 頁： 118 - 128 2020年1月

Saito, K; Okamoto, M; Watanabe, Y; Noguchi, N; Nagasaka, A; Nishina, Y; Shinoda, T; Sakakibara, A; Miyata, T

CELL REPORTS 29 巻 ( 6 ) 頁： 1555 - + 2019年11月

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 Reports

Embryonic radial glial fibers that guide most neocortical neurons are ventrally deflected near their terminal, contributing to further expansion of the neocortical area. Saito et al. demonstrate that this fiber deflection is induced physically by a previously unrecognized ventral stream of the earliest generated preplate neurons.

DOI： 10.1016/j.celrep.2019.09.075

Lzts1 controls both neuronal delamination and outer radial glial-like cell generation during mammalian cerebral development 査読有り国際誌

Kawaue T., Shitamukai A., Nagasaka A., Tsunekawa Y., Shinoda T., Saito K., Terada R., Bilgic M., Miyata T., Matsuzaki F., Kawaguchi A.

NATURE COMMUNICATIONS 10 巻 ( 1 ) 頁： 2780 - 2780 2019年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

In the developing central nervous system, cell departure from the apical surface is the initial and fundamental step to form the 3D, organized architecture. Both delamination of differentiating cells and repositioning of progenitors to generate outer radial glial cells (oRGs) contribute to mammalian neocortical expansion; however, a comprehensive understanding of their mechanisms is lacking. Here, we demonstrate that Lzts1, a molecule associated with microtubule components, promotes both cell departure events. In neuronally committed cells, Lzts1 functions in apical delamination by altering apical junctional organization. In apical RGs (aRGs), Lzts1 expression is variable, depending on Hes1 expression levels. According to its differential levels, Lzts1 induces diverse RG behaviors: planar division, oblique divisions of aRGs that generate oRGs, and their mitotic somal translocation. Loss-of-function of lzts1 impairs all these cell departure processes. Thus, Lzts1 functions as a master modulator of cellular dynamics, contributing to increasing complexity of the cerebral architecture during evolution.

DOI： 10.1038/s41467-019-10730-y

Differences in the Mechanical Properties of the Developing Cerebral Cortical Proliferative Zone between Mice and Ferrets at both the Tissue and Single-Cell Levels 査読有り

Elasticity-based boosting of neuroepithelial nucleokinesis via indirect energy transfer from mother to daughter

Shinoda Tomoyasu, Nagasaka Arata, Inoue Yasuhiro, Higuchi Ryo, Minami Yoshiaki, Kato Kagayaki, Suzuki Makoto, Kondo Takefumi, Kawaue Takumi, Saito Kanako, Ueno Naoto, Fukazawa Yugo, Nagayama Masaharu, Miura Takashi, Adachi Taiji, Miyata Takaki

PLOS BIOLOGY 16 巻 ( 4 ) 2018年4月

Elasticity-based boosting of neuroepithelial nucleokinesis via indirect energy transfer from mother to daughter.

Shinoda T, Nagasaka A, Inoue Y, Higuchi R, Minami Y, Kato K, Suzuki M, Kondo T, Kawaue T, Saito K, Ueno N, Fukazawa Y, Nagayama M, Miura T, Adachi T, Miyata T

PLoS biology 16 巻 ( 4 ) 頁： e2004426 2018年4月

Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics. 査読有り

Jin M, Pomp O, Shinoda T, Toba S, Torisawa T, Furuta K, Oiwa K, Yasunaga T, Kitagawa D, Matsumura S, Miyata T, Tan TT, Reversade B, Hirotsune S.

Scientific reports 7 巻頁： 39902 2017年1月

Synergistic action of nectins and cadherins generates the mosaic cellular pattern of the olfactory epithelium. 査読有り

Katsunuma S, Honda H, Shinoda T, Ishimoto Y, Miyata T, Kiyonari H, Abe T, Nibu K, Takai Y, Togashi H.

J Cell Biol 212 巻頁： 561-575 2016年2月

Nagasaka Arata, Shinoda Tomoyasu, Kawaue Takumi, Suzuki Makoto, Nagayama Kazuaki, Matsumoto Takeo, Ueno Naoto, Kawaguchi Ayano, Miyata Takaki

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 4 巻 ( NOV ) 頁： 139 2016年

Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. 査読有り

Tsuboi D, Kuroda K, Tanaka M, Namba T, Iizuka Y, Taya S, Shinoda T, Hikita T, Muraoka S, Iizuka M, Nimura A, Mizoguchi A, Shiina N, Sokabe M, Okano H, Mikoshiba K, Kaibuchi K.

Nat Neurosci. ( 18 ) 頁： 698-707 2015年5月

Interkinetic nuclear migration generates and opposes ventricular-zone crowding: insight into tissue mechanics 査読有り

Miyata, T; Okamoto, M; Shinoda, T; Kawaguchi, A

FRONTIERS IN CELLULAR NEUROSCIENCE 8 巻 ( 8 ) 頁： 473 2015年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Cellular Neuroscience

The neuroepithelium (NE) or ventricular zone (VZ), from which multiple types of brain cells arise, is pseudostratified. In the NE/VZ, neural progenitor cells are elongated along the apicobasal axis, and their nuclei assume different apicobasal positions. These nuclei move in a cell cycle-dependent manner, i.e., apicalward during G2 phase and basalward during G1 phase, a process called interkinetic nuclear migration (INM). This review will summarize and discuss several topics: the nature of the INM exhibited by neural progenitor cells, the mechanical difficulties associated with INM in the developing cerebral cortex, the community-level mechanisms underlying collective and efficient INM, the impact on overall brain formation when NE/VZ is overcrowded due to loss of INM, and whether and how neural progenitor INM varies among mammalian species. These discussions will be based on recent findings obtained in live, three-dimensional specimens using quantitative and mechanical approaches. Experiments in which overcrowding was induced in mouse neocortical NE/VZ, as well as comparisons of neocortical INM between mice and ferrets, have revealed that the behavior of NE/VZ cells can be affected by cellular densification. A consideration of the physical aspects in the NE/VZ and the mechanical difficulties associated with high-degree pseudostratification (PS) is important for achieving a better understanding of neocortical development and evolution.

DOI： 10.3389/fncel.2014.00473

Ferret-mouse differences in interkinetic nuclear migration and cellular densification in the neocortical ventricular zone 査読有り

Okamoto Mayumi, Shinoda Tomoyasu, Kawaue Takumi, Nagasaka Arata, Miyata Takaki

NEUROSCIENCE RESEARCH 86 巻頁： 88 - 95 2014年9月

Neurogenin2-d4Venus and Gadd45g-d4Venus transgenic mice: visualizing mitotic and migratory behaviors of cells committed to the neuronal lineage in the developing mammalian brain. 査読有り

Kawaue T, Sagou K, Kiyonari H, Ota K, Okamoto M, Shinoda T, Kawaguchi A, Miyata T.

Dev Growth Differ. ( 56 ) 頁： 293-304 2014年5月

Ferret-mouse differences in interkinetic nuclear migration and cellular densification in the neocortical ventricular zone. 査読有り

Okamoto M, Shinoda T, Kawaue T, Nagasaka A, Miyata T.

Neurosci Res. 頁： 88-95 2014年

TAG-1-assisted progenitor elongation streamlines nuclear migration to optimize subapical crowding. 査読有り

Okamoto M, Namba T, Shinoda T, Kondo T, Watanabe T, Inoue Y, Takeuchi K, Enomoto Y, Ota K, Oda K, Wada Y, Sagou K, Saito K, Sakakibara A, Kawaguchi A, Nakajima K, Adachi T, Fujimori T, Ueda M, Hayashi S, Kaibuchi K, Miyata T.

Nat Neurosci. ( 16 ) 頁： 1556-1566 2013年11月

Application of in utero electroporation and live imaging in the analyses of neuronal migration during mouse brain development 査読有り

Nishimura Yoshiaki V., Shinoda Tomoyasu, Inaguma Yutaka, Ito Hidenori, Nagata Koh-ichi

MEDICAL MOLECULAR MORPHOLOGY 45 巻 ( 1 ) 頁： 1 - 6 2012年3月

ROLE OF THE SEPTIN IN NEURAL CELL MIGRATION DURING BRAIN DEVELOPMENT 査読有り

Nagata K., Shinoda T., Nishimura Y. V, Ito H.

JOURNAL OF NEUROCHEMISTRY 118 巻頁： 169 - 169 2011年8月

Functional analysis of Dysbindin, a schizophrenia risk factor, in dendritic spine formation 査読有り

Ito H., Morishita R., Nishimura Y., Shinoda T., Iwamoto I., Nagata K-I.

MOLECULAR BIOLOGY OF THE CELL 22 巻 2011年

SCHIZOPHRENIA SUSCEPTIBILITY GENE, DYSBINDIN-1, REGULATES THE DENDRITIC SPINE FORMATION: EVIDENCE SUPPORTING NEURODEVELOPMENTAL HYPOTHESIS 査読有り

Ito H., Morishita R., Shinoda T., Iwamoto I., Sudo K., Nagata K.

JOURNAL OF NEUROCHEMISTRY 115 巻頁： 15 - 15 2010年10月

特集 SNARE複合体-膜融合の機構 SNARE複合体形成におけるセプチンの役割

伊東秀記, 篠田友靖, 永田浩一

生体の科学 61 巻 ( 3 ) 頁： 242 - 246 2010年6月

Septin 14 is involved in cortical neuronal migration via interaction with Septin 4. 査読有り

Shinoda T, Ito H, Sudo K, Iwamoto I, Morishita R, Nagata K

Molecular biology of the cell 21 巻 ( 8 ) 頁： 1324 - 34 2010年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Molecular Biology of the Cell

Septins are a family of conserved guanosine triphosphate/guanosine diphosphate-binding proteins implicated in a variety of cellular functions such as cell cycle control and cytokinesis. Although several members of septin family, including Septin 14 (Sept14), are abundantly expressed in nervous tissues, little is known about their physiological functions, especially in neuronal development. Here, we report that Sept14 is strongly expressed in the cortical plate of developing cerebral cortex. Knockdown experiments by using the method of in utero electroporation showed that reduction of Sept14 caused inhibition of cortical neuronal migration. Whereas cDNA encoding RNA interference-resistant Sept14 rescued the migration defect, the C-terminal deletion mutant of Sept14 did not. Biochemical analyses revealed that C-terminal coiled-coil region of Sept14 interacts with Septin 4 (Sept4). Knockdown experiments showed that Sept4 is also involved in cortical neuronal migration in vivo. In addition, knockdown of Sept14 or Sept4 inhibited leading process formation in migrating cortical neurons. These results suggest that Sept14 is involved in neuronal migration in cerebral cortex via interaction with Sept4. © 2010 by The American Society for Cell Biology.

DOI： 10.1091/mbc.e09-10-0869

Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation 査読有り

Ito Hidenori, Morishita Rika, Shinoda Tomoyasu, Sudo Kaori, Iwamoto Ikuko, Nagata Koh-ichi

NEUROSCIENCE RESEARCH 68 巻頁： E120 - E120 2010年

Septin 14 is involved in cortical neuronal migration via interaction with Septin 4 査読有り

Shinoda Tomoyasu, Ito Hidenori, Sudo Kaori, Iwamoto Ikuko, Morishita Rika, Nagata Koh-ichi

NEUROSCIENCE RESEARCH 68 巻頁： E251 - E251 2010年

Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein 査読有り

Hikita, T; Taya, S; Fujino, Y; Taneichi-Kuroda, S; Ohta, K; Tsuboi, D; Shinoda, T; Kuroda, K; Funahashi, Y; Uraguchi-Asaki, J; Hashimoto, R; Kaibuchi, K

JOURNAL OF NEUROCHEMISTRY 110 巻 ( 5 ) 頁： 1567 - 1574 2009年9月

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

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 dysbindin-interacting 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. © 2009 The Authors.

DOI： 10.1111/j.1471-4159.2009.06257.x

Sept14 is involved in the proper positioning of cortical pyramidal neuron 査読有り

Shinoda Tomoyasu, Ito Hidenori, Sudo Kaori, Iwamoto Ikuko, Morishita Rika, Nagata Koh-Ichi

NEUROSCIENCE RESEARCH 65 巻頁： S94 - S94 2009年

DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2 査読有り

Shinoda, T; Taya, S; Tsuboi, D; Hikita, T; Matsuzawa, R; Kuroda, S; Iwamatsu, A; Kaibuchi, K

JOURNAL OF NEUROSCIENCE 27 巻 ( 1 ) 頁： 4 - 14 2007年1月

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

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 14-3-3ε. 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. Copyright © 2007 Society for Neuroscience.

DOI： 10.1523/JNEUROSCI.3825-06.2007

DISC1 regulates the transport of the NUDEL/LIS1/14-3-3ε complex through Kinesin-1 査読有り

Taya, S; Shinoda, T; Tsuboi, D; Asaki, J; Nagai, K; Hikita, T; Kuroda, S; Kuroda, K; Shimizu, M; Hirotsune, S; Iwamatsu, A; Kaibuchi, K

JOURNAL OF NEUROSCIENCE 27 巻 ( 1 ) 頁： 15 - 26 2007年1月

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

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 14-3-3ε. 14-3-3ε 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/LIS1/14-3-3ε 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 14-3-3ε 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 14-3-3ε 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/LIS1/14-3-3ε complex into the axons as a cargo receptor for axon elongation. Copyright © 2007 Society for Neuroscience.

DOI： 10.1523/JNEUROSCI.3826-06.2006

Plexin-A4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance 査読有り

DISC1 interacts with RNA-binding proteins in messenger ribonucleoprotein complex 査読有り

Tsuboi D, Taya S, Shinoda T, Hikita T, Kuroda S, Kaibuchi K

JOURNAL OF PHARMACOLOGICAL SCIENCES 100 巻頁： 242P - 242P 2006年

Suto F, Ito K, Uemura M, Shimizu M, Shinkawa Y, Sanbo M, Shinoda T, Tsuboi M, Takashima S, Yagi T, Fujisawa H

JOURNAL OF NEUROSCIENCE 25 巻 ( 14 ) 頁： 3628 - 3637 2005年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Neuroscience

It has been proposed that four members of the plexin A subfamily (plexin-As; plexin-A1, -A2, -A3, and -A4) and two neuropilins (neuropilin-1 and neuropilin-2) form complexes and serve as receptors for class 3 secreted semaphorins (Semas), potent neural chemorepellents. The roles of given plexin-A4 in semaphorin signaling and axon guidance, however, are mostly unknown. Here, to elucidate functions of plexin-A4 in semaphorin signaling and axon guidance events in vivo, we generated plexin-A4 null mutant mice by targeted disruption of the plexin-A4 gene. Plexin-A4 mutant mice were defective in the trajectory and projection of peripheral sensory axons and sympathetic ganglion (SG) axons and the formation of the anterior commissure and the barrels. The defects in peripheral sensory and SG axons were fundamentally related to those of neuropilin-1 or Sema3A mutant embryos reported but were more moderate than the phenotype in these mutants. The growth cone collapse assay showed that dorsal root ganglion axons and SG axons of plexin-A4 mutant embryos partially lost their responsiveness to Sema3A. These results suggest that plexin-A4 plays roles in the propagation of Sema3A activities and regulation of axon guidance and that other members of the plexin-A subfamily are also involved in the propagation of Sema3A activities. Plexin-A4-deficient SG axons did not lose their responsiveness to Sema3F, suggesting that plexin-A4 serves as a Sema3A-specific receptor, at least in SG axons. In addition, the present study showed that plexin-A4 bound class 6 transmembrane semaphorins, Sema6A and Sema6B, and mediated their axon-repulsive activities, independently of neuropilin-1. Our results imply that plexin-A4 mediates multiple semaphorin signals and regulates axon guidance in vivo. Copyright © 2005 Society for Neuroscience.

DOI： 10.1523/JNEUROSCI.4480-04.2005