Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.

Cell
Authors
Keywords
Abstract

The Disrupted in Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

Year of Publication
2009
Journal
Cell
Volume
136
Issue
6
Pages
1017-31
Date Published
2009 Mar 20
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2008.12.044
PubMed ID
19303846
PubMed Central ID
PMC2704382
Links
Grant list
R01 NS037007 / NS / NINDS NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 NS037007-09 / NS / NINDS NIH HHS / United States
NS37007 / NS / NINDS NIH HHS / United States