Nature Cell Biology 7, 1167 - 1178 (2005)
Published online: 20 November 2005; | doi:10.1038/ncb1328
There is an Erratum (December 2005) associated with this Article.
A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex developmentAtsushi Kamiya1, 2, Ken-ichiro Kubo3, Toshifumi Tomoda4, 5, Manabu Takaki1, Richard Youn1, Yuji Ozeki1, 2, Naoya Sawamura1, Una Park6, Chikako Kudo3, 7, Masako Okawa2, Christopher A. Ross1, 6, 8, 9, Mary E. Hatten4, Kazunori Nakajima3, 7
& Akira Sawa1, 6, 91
Department of Psychiatry-Neurobiology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, CMSC 8-117, Baltimore, MD 21287, USA. 2
Department of Psychiatry, Shiga University of Medical Science, Seta tsukinowa-cho, Otsu, Shiga 520-21, Japan. 3
Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. 4
Laboratory of Developmental Neurobiology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. 5
Division of Neurosciences, Beckman Research Institute of the City of Hope, LA 91010, USA. 6
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 7
Department of Molecular Neurobiology, Institute of DNA Medicine, Jikei Univ. School of Medicine, Tokyo 105-8471, Japan. 8
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 9
Graduate Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Correspondence should be addressed to Akira Sawa asawa1@jhmi.edu Disrupted-In-Schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosomal translocation that is linked to a rare familial schizophrenia, has been genetically implicated in schizophrenia in other populations. Schizophrenia involves subtle cytoarchitectural abnormalities that arise during neurodevelopment, but the underlying molecular mechanisms are unclear. Here, we demonstrate that DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining the complex at the centrosome, hence contributing to normal microtubular dynamics. Carboxy-terminal-truncated mutant DISC1 (mutDISC1), which results from a chromosomal translocation, functions in a dominant-negative manner by redistributing wild-type DISC1 through self-association and by dissociating the DISC1–dynein complex from the centrosome. Consequently, either depletion of endogenous DISC1 or expression of mutDISC1 impairs neurite outgrowth in vitro and proper development of the cerebral cortex in vivo. These results indicate that DISC1 is involved in cerebral cortex development, and suggest that loss of DISC1 function may underlie neurodevelopmental dysfunction in schizophrenia.
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