title: Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.
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 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.
authors.affiliation: Howard Hughes Medical Institute, Cambridge, MA 02139, USA.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Mao
authors.forename: Xuecai
authors.initials: X
authors.lastname: Ge
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Frank
authors.forename: Jon M
authors.initials: JM
authors.lastname: Madison
authors.forename: Angela N
authors.initials: AN
authors.lastname: Koehler
authors.forename: Mary Kathryn
authors.initials: MK
authors.lastname: Doud
authors.forename: Carlos
authors.initials: C
authors.lastname: Tassa
authors.forename: Erin M
authors.initials: EM
authors.lastname: Berry
authors.forename: Takahiro
authors.initials: T
authors.lastname: Soda
authors.forename: Karun K
authors.initials: KK
authors.lastname: Singh
authors.forename: Travis
authors.initials: T
authors.lastname: Biechele
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Petryshen
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: 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*
chemical_list: 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