title: Common DISC1 polymorphisms disrupt Wnt/GSK3β signaling and brain development.
abstract: Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Karun K
authors.initials: KK
authors.lastname: Singh
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Rienzo
authors.forename: Laurel
authors.initials: L
authors.lastname: Drane
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Mao
authors.forename: Zachary
authors.initials: Z
authors.lastname: Flood
authors.forename: Jon
authors.initials: J
authors.lastname: Madison
authors.forename: Manuel
authors.initials: M
authors.lastname: Ferreira
authors.forename: Sarah
authors.initials: S
authors.lastname: Bergen
authors.forename: Cillian
authors.initials: C
authors.lastname: King
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.forename: Hazel
authors.initials: H
authors.lastname: Sive
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development*; D001923:Brain Chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics*; D060509:Wnt3A Protein / Q000235:genetics*; D015027:Zebrafish
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
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