TY - JOUR
T1 - Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3β/β-Catenin Signaling
AU - Mao, Yingwei
AU - Ge, Xuecai
AU - Frank, Christopher L.
AU - Madison, Jon M.
AU - Koehler, Angela N.
AU - Doud, Mary Kathryn
AU - Tassa, Carlos
AU - Berry, Erin M.
AU - Soda, Takahiro
AU - Singh, Karun K.
AU - Biechele, Travis
AU - Petryshen, Tracey L.
AU - Moon, Randall T.
AU - Haggarty, Stephen J.
AU - Tsai, Li Huei
N1 - Funding Information:
We thank A. Sawa for providing the human DISC1 cDNA construct, C. Lois for the FUGW construct, X. He for FLAG-Dvl2, HA-GSK3β, FLAG-WT-β-catenin, and SA-β-catenin constructs, Y. Ma and M. Greenberg for Ngn2 antibodies, and F. Gage for the AHP cells. We acknowledge E. Scolnick, B.A. Samuels, Z. Xie, D. Meletis, M. Carlen, C. Bragg, J. Buchman, P. Thanawala, and M. Dobbin for technical support, helpful discussion, and critical reading of the manuscript. L.-H.T. is an investigator of the Howard Hughes Medical Institute and the director of the neurobiology program at the Stanley Center for Psychiatric Research. Y.M. is a recipient of the National Alliance for Research on Schizophrenia and Depression Young Investigator Award. K.K.S. is a recipient of a Natural Sciences and Engineering Research Council Postdoctoral Award and a Human Frontiers Science Program Research Fellowship. T.S. is a recipient of the Singleton Fellowship. This work was partially supported by a National Institutes of Health grant (NS37007) to L.-H.T.
PY - 2009/3/20
Y1 - 2009/3/20
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/62149083806
UR - https://www.scopus.com/inward/citedby.url?scp=62149083806&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2008.12.044
DO - 10.1016/j.cell.2008.12.044
M3 - Article
C2 - 19303846
AN - SCOPUS:62149083806
SN - 0092-8674
VL - 136
SP - 1017
EP - 1031
JO - Cell
JF - Cell
IS - 6
ER -