Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3 beta/beta-Catenin Signaling

作者：Mao Yingwei; Ge Xuecai; Frank Christopher L; Madison Jon M; Koehler Angela N; Doud Mary Kathryn; Tassa Carlos; Berry Erin M; Soda Takahiro; Singh Karun K; Biechele Travis; Petryshen Tracey L; Moon Randall T; Haggarty Stephen J; Tsai Li Huei^*

来源：Cell, 2009, 136(6): 1017-1031.

DOI：10.1016/j.cell.2008.12.044

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 GSK3 beta. First, DISC1 inhibits GSK3 beta 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 inGSK3 beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

• 出版日期2009-3-20