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

Article

关键词: SCHIZOPHRENIA 1;    CELL POLARITY;    ZEBRAFISH;    EXPRESSION;    MECHANISM;    BRAIN;    DISRUPTED-IN-SCHIZOPHRENIA-1;    XENOPUS;    ABNORMALITIES;    GASTRULATION;   

DOI  :  10.1096/fj.11-186239

来源: SCIE

【 摘 要 】

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 GSK3 beta, and zDisc1 directs early brain development and neurogenesis, by promoting beta-catenin-mediated Wnt signaling and inhibiting GSK3 beta 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 GSK3 beta construct, suggesting that zDisc1 inhibits GSK3 beta 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.-De Rienzo, G., Bishop, J. A., Mao, Y., Pan, L., Ma, T. P., Moens, C. B., Tsai, L. H., Sive, H. Disc1 regulates both beta-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis. FASEB J. 25, 4184 -4197 (2011). www.fasebj.org

【 授权许可】

Free