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Cell DOI:10.1016/j.cell.2008.12.044

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

Publication TypeJournal Article
Year of Publication2009
AuthorsMao, Y, Ge, X, Frank, CL, Madison, JM, Koehler, AN, Doud, MKathryn, Tassa, C, Berry, EM, Soda, T, Singh, KK, Biechele, T, Petryshen, TL, Moon, RT, Haggarty, SJ, Tsai, L-H
Date Published2009 Mar 20
KeywordsAdult Stem Cells, Animals, beta Catenin, Brain, Embryo, Mammalian, Gene Knockdown Techniques, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neurogenesis, Neurons, Signal Transduction, Stem Cells

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.


Alternate JournalCell
PubMed ID19303846
PubMed Central IDPMC2704382
Grant ListR01 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