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A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development

Nature Cell Biology volume 7, pages 1167–1178 (2005)Cite this article

An Erratum to this article was published on 02 December 2005

Abstract

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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Figure 1: DISC1 regulates the dynein protein complex at the centrosome and modulates microtubular dynamics.
Figure 2: Influence of DISC1 in microtubular reorganization in COS-7 cells.
Figure 3: mutDISC1 functions in a dominant-negative manner via its self-association domain.
Figure 4: MutDISC1 affects a key function of wtDISC1 in anchoring the dynein motor proteins at the centrosome.
Figure 5: Requirement of DISC1 for neurite outgrowth in neuronal cells.
Figure 6: Essential role of DISC1 in proper neuronal migration of the developing cerebral cortex in vivo.
Figure 7: mutDISC1 impairs proper neurodevelopment in the cerebral cortex in vivo.

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Acknowledgements

We thank Y. Lema for preparation of the figures. We thank P. Talalay, D. Solecki, T. Sedlak, N. Katsanis, J. Cheah and S. Snyder for critical reading of the manuscript. We thank T. Oe for technical support of the neurite outgrowth assay, and M. Peak for technical assistance. This work was supported by a U.S. Public Health Service Grant (MH-069853) to A.S. It was also supported by foundation grants from NARSAD, Stanley, S-R and funds from the departments (A.S.); NARSAD and Stanley (C.A.R.); MEXT, JSPS, Kanehara, Casio, Novaltis and Sumitomo foundations (K.N.).

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Authors and Affiliations

  1. Department of Psychiatry-Neurobiology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, CMSC 8-117, Baltimore, 21287, MD, USA

    Atsushi Kamiya, Manabu Takaki, Richard Youn, Yuji Ozeki, Naoya Sawamura, Christopher A. Ross & Akira Sawa

  2. Department of Psychiatry, Shiga University of Medical Science, Seta tsukinowa-cho, Otsu, Shiga, 520-21, Japan

    Atsushi Kamiya, Yuji Ozeki & Masako Okawa

  3. Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Ken-ichiro Kubo, Chikako Kudo & Kazunori Nakajima

  4. Laboratory of Developmental Neurobiology, The Rockefeller University, 1230 York Avenue, New York, 10021, NY, USA

    Toshifumi Tomoda & Mary E. Hatten

  5. Division of Neurosciences, Beckman Research Institute of the City of Hope, 91010, LA, USA

    Toshifumi Tomoda

  6. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Una Park, Christopher A. Ross & Akira Sawa

  7. Department of Molecular Neurobiology, Institute of DNA Medicine, Jikei Univ. School of Medicine, Tokyo, 105-8471, Japan

    Chikako Kudo & Kazunori Nakajima

  8. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA

    Christopher A. Ross

  9. Graduate Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Christopher A. Ross & Akira Sawa

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Correspondence to Akira Sawa.

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Kamiya, A., Kubo, Ki., Tomoda, T. et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 7, 1167–1178 (2005). https://doi.org/10.1038/ncb1328

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