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 RIS Download
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