A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development

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 wildtype 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. DISC1 was originally identified as the sole disrupted gene that has an open reading frame at the breakpoint of a balanced chromosomal translocation, which was inherited in a large Scottish pedigree 1 . Most of the family members with the chromosomal abnormality have major mental illnesses, including schizophrenia. These illnesses have been diagnosed according to the criteria of DSM-IV, and it has been shown that they have no physical, neurological or dysmorphic conditions 2 . The patients display a reduction in the amplitude of the P300 event-related potential, which is frequently observed in general schizophrenia. Lack of available autopsied brains from this Scottish family has hampered further understanding of the role of DISC1 in the pathophysiology of their mental conditions. The balanced translocation could lead to production of a carboxy-terminal truncated DISC1 mutant protein (mutDISC1) or haploinsufficiency due to instability of the DISC1 protein from the disrupted chromosome. Recent linkage and association studies also indicate that DISC1 has a role in schizophrenia in general populations 3–6 . Therefore, understanding of the molecular and cellular roles of DISC1 may provide insight into the pathology of schizophrenia. The neurodevelopmental aetiology of schizophrenia has indicated that enlargement of ventricles occurs, with the presence of mild cytoarchitectural abnormalities and no signs of gliosis 7–11 . Such defects