Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling
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Mao-2009-Disrupted in Schizop.pdf
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Author(s)
Mao, Yingwei
Ge, Xuecai
Frank, Christopher Lee
Madison, Jon M.
Koehler, Angela Nicole
Doud, Mary Kathryn
Tassa, Carlos
Berry, Erin M.
Soda, Takahiro
Singh, Karun K.
Date Issued
March 2009
Journal
Cell
Publisher
Elsevier
Citation
Mao, Yingwei, Xuecai Ge, Christopher L. Frank, Jon M. Madison, Angela N. Koehler, Mary Kathryn Doud, Carlos Tassa, et al. “Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling.” Cell 136, no. 6 (March 2009): 1017–1031. © 2009 Elsevier Inc.
Version
Final published version
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 GSK3β. First, DISC1 inhibits GSK3β activity through direct physical interaction, which reduces β-catenin phosphorylation and stabilizes β-catenin. Importantly, expression of stabilized β-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 GSK3β/β-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1016/j.cell.2008.12.044
