記述言語：英語   出版者・発行元：Molecular Psychiatry  

DOI： 10.1038/mp.2010.93

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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

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

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

掲載種別：研究論文（学術雑誌）  

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：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

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/jourrnal.pbio.2004426

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pbio.2004426

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep39902.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 561-575

掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Cell and Developmental Biology  

DOI： 10.3389/fcell.2016.00139

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/nn.3984.

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：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

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

DOI： 10.1016/j.neures.2014.10.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/dgd.12131.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/nn.3525.

掲載種別：研究論文（学術雑誌）   出版者・発行元：Medical Molecular Morphology  

DOI： 10.1007/s00795-011-0557-0

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.2425100991

CiNii Research

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

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neures.2010.07.2101

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neures.2010.07.1113

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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 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

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neures.2009.09.395

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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  

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

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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  

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

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掲載種別：研究論文（学術雑誌）  

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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

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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CiNii Books

記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）  

DOI： 10.1038/nn.3525.

記述言語：英語   出版者・発行元：日本神経化学会