Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling
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.; Biechele, Travis; Petryshen, Tracey L.; Moon, Randall T.; Haggarty, Stephen J.; Tsai, Li-Huei; ... Show more Show less
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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.
DepartmentHarvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Picower Institute for Learning and Memory
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.
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