title: Disc1 regulates both β-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis.
abstract: Disc1 is a schizophrenia risk gene that engages multiple signaling pathways during neurogenesis and brain development. Using the zebrafish as a tool, we analyze the function of zebrafish Disc1 (zDisc1) at the earliest stages of brain and body development. We define a "tool" as a biological system that gives insight into mechanisms underlying a human disorder, although the system does not phenocopy the disorder. A zDisc1 peptide binds to GSK3β, and zDisc1 directs early brain development and neurogenesis, by promoting β-catenin-mediated Wnt signaling and inhibiting GSK3β activity. zDisc1 loss-of-function embryos additionally display a convergence and extension phenotype, demonstrated by abnormal movement of dorsolateral cells during gastrulation, through changes in gene expression, and later through formation of abnormal, U-shaped muscle segments, and a truncated tail. These phenotypes are caused by alterations in the noncanonical Wnt pathway, via Daam and Rho signaling. The convergence and extension phenotype can be rescued by a dominant negative GSK3β construct, suggesting that zDisc1 inhibits GSK3β activity during noncanonical Wnt signaling. This is the first demonstration that Disc1 modulates the noncanonical Wnt pathway and suggests a previously unconsidered mechanism by which Disc1 may contribute to the etiology of neuropsychiatric disorders.
authors.affiliation: Whitehead institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Rienzo
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bishop
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Mao
authors.forename: Luyuan
authors.initials: L
authors.lastname: Pan
authors.forename: Taylur P
authors.initials: TP
authors.lastname: Ma
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Moens
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.forename: Hazel
authors.initials: H
authors.lastname: Sive
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000196:embryology / Q000378:metabolism; D017124:Conserved Sequence; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013045:Species Specificity; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C538728:DISC1 protein, zebrafish; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D029961:Zebrafish Proteins; D051176:beta Catenin; C495269:ctnnb1 protein, zebrafish; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3