De Rienzo, G., Bishop, J.A., Mao, Y., Pan, L., Ma, T.P., Moens, C.B., Tsai, L.H., and Sive, H. (2011) Disc1 regulates both β-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 25(12):4184-97.
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.