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Disc1 regulates both β-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis.

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.

Pubmed ID: 21859895


  • De Rienzo G
  • Bishop JA
  • Mao Y
  • Pan L
  • Ma TP
  • Moens CB
  • Tsai LH
  • Sive H


FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Data

December 1, 2011

Associated Grants

  • Agency: NICHD NIH HHS, Id: R01 HD076585
  • Agency: NHGRI NIH HHS, Id: R01 HG002995
  • Agency: NIMH NIH HHS, Id: R01 MH091115

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Binding Sites
  • Brain
  • Conserved Sequence
  • DNA Primers
  • Embryonic Development
  • Glycogen Synthase Kinase 3
  • Humans
  • Mutagenesis
  • Nerve Tissue Proteins
  • Neurogenesis
  • Oligodeoxyribonucleotides, Antisense
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Species Specificity
  • Wnt Signaling Pathway
  • Zebrafish
  • Zebrafish Proteins
  • beta Catenin