Disc1 Regulates Both β-catenin-mediated and Noncanonical Wnt Signaling During Vertebrate Embryogenesis

FASEB J. 2011 Dec;25(12):4184-97. doi: 10.1096/fj.11-186239. Epub 2011 Aug 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • DISC1 protein, zebrafish
  • DNA Primers
  • Nerve Tissue Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Zebrafish Proteins
  • beta Catenin
  • ctnnb1 protein, zebrafish
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3