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Disrupted-in-Schizophrenia-1 (DISC-1): Mutant Truncation Prevents Binding to NudE-like (NUDEL) and Inhibits Neurite Outgrowth
Yuji Ozeki, Toshifumi Tomoda, John Kleiderlein, Atsushi Kamiya, Lyuda Bord, Kumiko Fujii, Masako Okawa, Naoto Yamada, Mary E. Hatten, Solomon H. Snyder, Christopher A. Ross and Akira Sawa
Proceedings of the National Academy of Sciences of the United States of America
Vol. 100, No. 1 (Jan. 7, 2003), pp. 289-294
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3074148
Page Count: 6
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Disrupted-in-Schizophrenia-1 (DISC-1) is a gene whose mutant truncation is associated with major psychiatric illness with a predominance of schizophrenic symptomatology. We have cloned and characterized rodent DISC-1. DISC-1 expression displays pronounced developmental regulation with the highest levels in late embryonic life when the cerebral cortex develops. In yeast two-hybrid analyses, DISC-1 interacts with a variety of cytoskeletal proteins. One of these, NudE-like (NUDEL), is associated with cortical development and is linked to LIS-1, the disease gene for a form of lissencephaly, a disorder of cortical development. The disease mutant form of DISC-1 fails to bind NUDEL. Expression of mutant, but not wild-type, DISC-1 in PC12 cells reduces neurite extension. As schizophrenia is thought to reflect defects in cortical development that are determined by cytoskeletal protein activities, the cellular disturbances we observe with mutant DISC-1 may be relevant to psychopathologic mechanisms.
Proceedings of the National Academy of Sciences of the United States of America © 2003 National Academy of Sciences