事業推進担当者: 仲嶋 一範 (なかじま かずのり)

事業推進担当者 | 特別研究教員 | RA・特別研究員

仲嶋 一範 (なかじま かずのり)

慶應義塾大学医学部解剖学教室教授、東京慈恵会医科大学客員教授

昭和38年生
慶應義塾大学医学部解剖学教室
〒160-8582 東京都新宿区信濃町35
FAX:03-5379-1977
E-mail:kazunori@sc.itc.keio.ac.jp
URL:http://web.sc.itc.keio.ac.jp/anatomy/
nakajima/index.html

略歴

1988年3月 慶應義塾大学医学部卒業
1990年3月 慶應義塾大学病院内科研修修了
1994年3月 大阪大学大学院医学研究科博士課程修了
1994年4月 日本学術振興会特別研究員(PD)
1995年4月 理化学研究所ライフサイエンス筑波研究センター分子神経生物学研究室研究員
1996年2月 米国聖ジュード小児研究病院発生神経生物学部客員研究員(兼任)
1997年10月 理化学研究所脳科学総合研究センター研究員(兼任)
1998年9月 東京慈恵会医科大学DNA医学研究所分子神経生物学研究部門長・講師
1999年10月 科学技術振興事業団さきがけ研究21研究員(兼任)
2001年5月 東京慈恵会医科大学DNA医学研究所分子神経生物学研究部門長・助教授
2002年4月 慶應義塾大学医学部解剖学教室教授、東京慈恵会医科大学客員教授

資格・学位

1988年 医師免許
1994年 博士(医学)(大阪大学)

主たる研究領域

発生神経生物学

主たる所属学会

日本神経化学会、日本神経科学学会、日本発生生物学会、日本解剖学会、日本分子生物学会、Society for Neuroscience(北米神経科学会)

審査会歴/委員等

総務省「戦略的情報通信研究開発推進制度」専門評価委員、日本学術振興会特別研究員等審査会専門委員、内閣府沖縄科学技術大学院大学「ブレインストーミング会合」「Scientific Working Group」メンバー、日本学術振興会科学研究費委員会専門委員、理化学研究所外部評価委員等

学術誌編集

"The Keio Journal of Medicine" Editorial Advisory Board (2002~)
"Developmental Brain Research" Editorial Board(2002~2005)
"Molecular and Cellular Biochemistry" Editorial Board(2004~)
"Brain Research" Editorial Board(2006~)

COE分担課題と研究活動

大脳皮質層形成の成立と破綻の分子細胞機構解明

我々ヒトをはじめとする哺乳類は、大脳皮質を高次脳機能の中枢として発達させる。大脳皮質内の神経細胞群は、興奮性神経細胞と抑制性神経細胞とがバランス良く配置されており、さらに共通の特徴を有する神経細胞同士が集合して、整然とした多層構造を形成している。この構造を発生過程において正しく形作ることは、正常に脳が機能するためには極めて重要なプロセスである。本研究では、この大脳皮質を構成する神経細胞がその誕生部位からどのような機構で最終配置部位へと移動し、その後整然とした層構造を形成していくのかを、特にシステムとしての細胞内外機構の連携という視点から明らかにすることを目指す。

研究の概要

大脳皮質では、興奮性神経細胞の多くは脳室面近くで誕生し、脳表面の辺縁帯直下まで放射状に移動してその移動を終える。その過程を繰り返すことにより、早生まれの神経細胞ほど最終的により深層に配置され、遅生まれの神経細胞ほどより浅層に配置される("inside-out"様式)。その結果、脳表面に平行な6層から成る見事な多層構造が形成される。一方、大脳皮質の抑制性神経細胞の多くは腹側の基底核原基で誕生し、脳表面に平行に皮質(外套)に侵入するが、興味深いことにこれらも皮質内においては誕生日に依存して"inside-out"様式で各層に配置されるという特徴がある。
そこで我々は、
(1) 神経細胞誕生時において、その後の挙動・最終配置に関していかなる制御が行われるのか?
(2) 神経細胞の誕生部位から最終配置部位への移動は、どのような制御を受けて正しく行われるのか?
(3) 最終配置部位において移動を終え、分化成熟して見事に整然と配列する仕組み(特に細胞間相互作用と細胞外シグナルによる制御)はどうなっているのか?
の主として3つの側面から、機能的神経細胞社会の形成機構の解明を目指した研究を行っている。
(詳細及び最新の情報については、研究室ホームページをご参照下さい。)

主な研究業績

Identification of molecules preferentially expressed beneath the marginal zone in the developing cerebral cortex. Kashiko Tachikawa, Shinji Sasaki, Takuya Maeda, and Kazunori Nakajima. Neurosci. Res., in press.

Migratory behavior of presumptive interneurons is affected by AMPA receptor activation in slice cultures of embryonic mouse neocortex. Masato Yozu, Hidenori Tabata, Norbert Koenig, and Kazunori Nakajima. Dev. Neurosci., 30 (1-3), 105-116 (2008).

Computational cell model based on autonomous cell movement regulated by cell-cell signalling successfully recapitulates the "inside and outside" pattern of cell sorting. Takuya T Maeda, Itsuki Ajioka, and Kazunori Nakajima. BMC Systems Biology, 1, 43 (16 pages) (2007).

Regulation of the interaction of Disabled-1 with CIN85 by phosphorylation with Cyclin-dependent kinase 5. Yutaka Sato, Masato Taoka, Nami Sugiyama, Kenichiro Kubo, Takahiro Fuchigami, Akiko Asada, Taro Saito, Kazunori Nakajima, Toshiaki Isobe, and Shin-ichi Hisanaga. Genes to Cells,12 (12), 1315-1327 (2007).

Control of tangential/non-radial migration of neurons in the developing cerebral cortex. Kazunori Nakajima Neurochem. Int., 51 (2-4), 121-131 (2007).

The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling. Yoshimi Nakano, Takao Kohno, Terumasa Hibi, Shiori Kohno, Atsushi Baba, Katsuhiko Mikoshiba, Kazunori Nakajima, and Mitsuharu Hattori. J. Biol. Chem., 282 (28), 20544-20552 (2007).

Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex. Toshio Ohshima, Motoyuki Hirasawa, Hidenori Tabata, Tetsuji Mutoh, Tomoko Adachi, Hiromi Suzuki, Keiko Saruta, Takuji Iwasato, Shigeyoshi Itohara, Mitsuhiro Hashimoto, Kazunori Nakajima, Masaharu Ogawa, Ashok B. Kulkarni and Katsuhiko Mikoshiba. Development, 134 (12), 2273-2282 (2007).

Neurogenesis. Koji Oishi and Kazunori Nakajima. Encyclopedic Reference of Neuroscience, Springer-Verlag, in press.

Expression profiles of Insulin-like growth factor binding protein-like 1 in the developing mouse forebrain. Yuko Gonda, Hitoshi Sakurai, Yukio Hirata, Hidenori Tabata, Itsuki Ajioka, and Kazunori Nakajima. Gene Expr. Patterns,7 (4), 431-440 (2007).

Mouse Disabled1 (Dab1) is a nucleocytoplasmic shuttling protein. Takao Honda and Kazunori Nakajima. J. Biol. Chem., 281 (50), 38951-38965 (2006).

Large-scale correlation of DNA accession numbers to the cDNAs in the FANTOM full-length mouse cDNA clone set. Itsuki Ajioka*, Takuya Maeda*, and Kazunori Nakajima Keio J. Med., 55 (3), 107-110 (2006). (*equal contributors)

Identification of ventricular-side-enriched molecules regulated in a stage-dependent manner during cerebral cortical development. Itsuki Ajioka, Takuya Maeda, and Kazunori Nakajima Eur. J. Neurosci., 23(2), 296-308 (2006).

Disrupted-In-Schizophrenia-1 in development of the cerebral cortex: perturbation by its schizophrenia-associated mutation. Atsushi Kamiya, Ken-ichiro Kubo, Toshifumi Tomoda, Manabu Takaki, Richard Youn, Yuji Ozeki, Naoya Sawamura, Una Park, Chikako Kudo, Masako Okawa, Christopher A. Ross, Mary E. Hatten, Kazunori Nakajima, and Akira Sawa. Nature Cell Biol., 7 (12), 1067-1078 (2005).

Switching of α-catenin from αE-catenin in the cortical ventricular zone to αN-catenin II in the intermediate zone. Itsuki Ajioka and Kazunori Nakajima. Dev. Brain Res., 160(1),106-111 (2005).

The caudal migratory stream: A novel migratory stream of interneurons derived from the caudal ganglionic eminence in the developing mouse forebrain. Masato Yozu, Hidenori Tabata, and Kazunori Nakajima. J. Neurosci., 25 (31), 7268-7277 (2005).

Birthdate-dependent-segregation of the mouse cerebral cortical neurons in reaggregation cultures. Itsuki Ajioka and Kazunori Nakajima. Eur. J. Neurosci., 22 (2), 331-342 (2005).

Expression profiles of EphA3 at both the RNA and protein level in the developing mammalian forebrain. Chikako Kudo, Itsuki Ajioka, Yukio Hirata, and Kazunori Nakajima. J. Comp. Neurol., 487 (3), 255-269 (2005).

Neuronal migration in cortical development. Shigeaki Kanatani, Hidenori Tabata, and Kazunori Nakajima. J. Child Neurol., 20 (4), 274-279 (2005).

Birth-date dependent alignment of GABAergic neurons occurs in a different pattern from that of non-GABAergic neurons in the developing mouse visual cortex. Masato Yozu, Hidenori Tabata, and Kazunori Nakajima. Neurosci. Res., 49 (4), 395-403 (2004).

The Wnt/β-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Yusuke Hirabayashi, Yasuhiro Itoh, Hidenori Tabata, Kazunori Nakajima, Tetsu Akiyama, Norihisa Masuyama and Yukiko Gotoh. Development, 131 (12), 2791-2801 (2004).

Components of the Reelin signaling pathway are expressed in the spinal cord. Yee Ping Yip, Christine Capriotti, Susan Magdaleno, David Benhayon, Tom Curran, Kazunori Nakajima, and Joseph W. Yip. J. Comp. Neurol., 470 (2), 210-219 (2004).

Multipolar migration: the third mode of radial neuronal migration in the developing cerebral cortex. Hidenori Tabata and Kazunori Nakajima. J. Neurosci., 23 (31), 9996-10001 (2003).

Segregation and coactivation of developing neocortical layer 1 neurons. Takeshi Soda, Ryo Nakashima, Dai Watanabe, Kazunori Nakajima, Ira Pastan, and Shigetada Nakanishi. J. Neurosci., 23 (15), 6272-6279 (2003).

Cellular and molecular mechanisms of neuronal migration in neocortical development. Takao Honda, Hidenori Tabata, and Kazunori Nakajima. Sem. in Cell & Develop. Biol., 14 (3), 169-174 (2003).

Cell and molecular mechanisms that control cortical layer formation in the brain. Ken-ichiro Kubo and Kazunori Nakajima. Keio J. Med., 52 (1), 8-20 (2003).

Neurons tend to stop migration and differentiate along the cortical internal plexiform zones in the Reelin signal-deficient mice. Hidenori Tabata and Kazunori Nakajima. J. Neurosci. Res., 69, 723-730, (2002).

Secreted Reelin molecules form homodimers. Ken-ichiro Kubo, Katsuhiko Mikoshiba, and Kazunori Nakajima. Neurosci. Res., 43, 381-388 (2002).

Efficient in utero gene transfer system to the developing mouse brains using electroporation-- Visualization of neuronal migration in the developing cortex. Hidenori Tabata and Kazunori Nakajima. Neuroscience, 103, 865-872 (2001).

Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody. Naoko Utsunomiya-Tate, Ken-ichiro Kubo, Shin-ichi Tate, Masatsune Kainosho, Eisaku Katayama, Kazunori Nakajima*, and Katsuhiko Mikoshiba. Proc. Natl. Acad. Sci. U.S.A., 97, 9729-9734 (2000). (*corresponding author)

Reelin controls position of autonomic neurons in the spinal cord. Joseph W. Yip, Yee Ping L. Yip, Kazunori Nakajima, Christine Capriotti. Proc. Natl. Acad. Sci. U.S.A., 97, 8612-8616 (2000).

The disabled 1 gene is disrupted by a replacement with L1 fragment in yotari mice. Toshio Kojima, Kazunori Nakajima*, and Katsuhiko Mikoshiba. Mol. Brain Res., 75, 121-127 (2000). (*corresponding author)

Thyroid hormone regulates reelin and dab1 expression during brain development. Manuel Alvarez-Dolado, Monica Ruiz, Jose A. del Rio, Soledad Alcantara, Ferran Burgaya, Michael Sheldon, Kazunori Nakajima, Juan Bernal, Brian W. Howell, Tom Curran, Eduardo Soriano, and Alberto Munoz. J. Neurosci., 19, 6979-6993 (1999).

Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. S. Hossein Fatemi, Effat-Sadat Emamian, David Kist, Robert W. Sidwell, Kazunori Nakajima, Pervez Akhter, Anna Shier, Soheil Sheikh, and K. Bailey. Molecular Psychiatry, 4, 145-154 (1999).

Reelin regulates the development and synaptogenesis of the layer-specific entorhino-hippocampal connections. Victor Borrell, Jose A. Del Rio, Soledad Alcantara, Michele Derer, Albert Martinez, Gabriella D'Arcangelo, Kazunori Nakajima, Katsuhiko Mikoshiba, Paul Derer, Tom Curran, and Eduardo Soriano. J. Neurosci., 19, 1345-1358 (1999).

Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Dennis S. Rice, Michael Sheldon, Gabriella D'Arcangelo, Kazunori Nakajima, Dan Goldowitz, and Tom Curran. Development, 125, 3719-3729 (1998).

A truncated Reelin protein is produced but not secreted in the "Orleans" reeler mutation (Relnrl-Orl). Vinciane de Bergeyck, Kazunori Nakajima*, C. Lambert de Rouvroit, B. Naerhuyzen, Andre M. Goffinet, Takaki Miyata, Masaharu Ogawa, and Katsuhiko Mikoshiba. Mol. Brain Res., 50, 85-90 (1997). (*co-first author and corresponding author)

A novel neurological mutation of mouse, yotari, which exhibits reeler-like phenotype but expresses CR-50 antigen/Reelin. Hiroyuki Yoneshima, Eiichiro Nagata, Mineo Matsumoto, Maki Yamada, Kazunori Nakajima, Takaki Miyata, Masaharu Ogawa, and Katsuhiko Mikoshiba. Neurosci. Res. 29, 217-223 (1997).

scrambler and yotaridisrupt the disabled gene and produce a reeler -like phenotype in mice. Michael Sheldon, Dennis Rice, Gabriella D'Arcangelo, Hiroyuki Yoneshima, Kazunori Nakajima, Katsuhiko Mikoshiba, Brian W. Howell, Jonathan A. Cooper, Dan Goldowitz, and Tom Curran. Nature 389, 730-733 (1997).

Disruption of hippocampal development in vivo by CR-50, a monoclonal antibody against Reelin. Kazunori Nakajima*, Katsuhiko Mikoshiba, Takaki Miyata, Chikako Kudo, and Masaharu Ogawa. Proc. Natl. Acad. Sci. U.S.A. 94, 8196-8201 (1997). (*corresponding author)

Regulation of Purkinje cell alignment by Reelin as revealed with CR-50 antibody. Takaki Miyata, Kazunori Nakajima, Katsuhiko Mikoshiba, and Masaharu Ogawa. J. Neurosci. 17, 3599-3609 (1997).

A role for Cajal-Retzius cells and reelin in the development of hippocampal connections. Jose A. Del Rio, Bernd Heimrich, Victor Borrell, Eckart Foerster, Alexander Drakew, Soledad Alcantara, Kazunori Nakajima, Takaki Miyata, Masaharu Ogawa, Katsuhiko Mikoshiba, Paul Derer, Michael Frotscher, and Eduardo Soriano. Nature 385, 70-74 (1997).

Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. Gabriella D'Arcangelo, Kazunori Nakajima, Takaki Miyata, Masaharu Ogawa, Katsuhiko Mikoshiba, and Tom Curran. J. Neurosci. 17, 23-31 (1997).

Astrocyte lineage analysis by detection of GFAP promoter activity in vitro. Noriyuki Morita, Kensuke Nakahira, Hiroko Baba, Hiromi Akita, Tatsuro Kumada, Masaharu Ogawa, Kazunori Nakajima, Mitsuhiro Kawata, Katsuhiko Mikoshiba, and Kazuhiro Ikenaka. Dev. Neurosci. 19, 210-218 (1997).

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