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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Mao, Y; Ge, X; Frank, CL; Madison, JM; Koehler, AN; Doud, MK; Tassa, C; Berry, EM; Soda, T; Singh, KK; Biechele, T; Petryshen, TL; Moon, RT; Haggarty, SJ; Tsai, L-H

Published Date

  • March 20, 2009

Published In

Volume / Issue

  • 136 / 6

Start / End Page

  • 1017 - 1031

PubMed ID

  • 19303846

Pubmed Central ID

  • PMC2704382

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2008.12.044


  • eng

Conference Location

  • United States