Disc1 regulates both β-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis
- Authors
- De Rienzo, G., Bishop, J.A., Mao, Y., Pan, L., Ma, T.P., Moens, C.B., Tsai, L.H., and Sive, H.
- ID
- ZDB-PUB-110901-1
- Date
- 2011
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25(12): 4184-97 (Journal)
- Registered Authors
- De Rienzo, Gianluca, Ma, Taylur, Moens, Cecilia, Pan, Luyuan, Sive, Hazel
- Keywords
- Disc1, zebrafish, brain, neurons, G5K3β
- 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
- 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*
- PubMed
- 21859895 Full text @ FASEB J.
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.