Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.
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.
Mao
Yingwei
Y
Howard Hughes Medical Institute, Cambridge, MA 02139, USA.
Ge
Xuecai
X
Frank
Christopher L
CL
Madison
Jon M
JM
Koehler
Angela N
AN
Doud
Mary Kathryn
MK
Tassa
Carlos
C
Berry
Erin M
EM
Soda
Takahiro
T
Singh
Karun K
KK
Biechele
Travis
T
Petryshen
Tracey L
TL
Moon
Randall T
RT
Haggarty
Stephen J
SJ
Tsai
Li-Huei
LH
D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology; D004622:Embryo, Mammalian / Q000378:metabolism; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3