DISC1 partners with GSK3beta in neurogenesis

Abstract

The protein DISC1, encoded by a gene implicated in schizophrenia susceptibility, regulates the development of postmitotic neurons. Mao et al. (2009) now report that DISC1 also regulates the proliferation of embryonic and adult neural progenitor cells through the GSK3beta/beta-catenin pathway, providing new insights into how susceptibility genes may contribute to the etiology of psychiatric disorders.

Figure 1.. Regulation of Neurogenesis by DISC1

The model shows how DISC1 may regulate different steps in neurogenesis in embryonic and adult mouse brain. DISC1 inhibits GSK3β through its N-terminal domain, which results in stabilization of β-catenin and activation of downstream transcription factors. These factors promote proliferation of neural progenitor cells, preventing their premature exit from the cell cycle and neuronal differentiation. A candidate pathway working upstream of GSK3β is the Wnt signaling pathway, which regulates autophosphorylation of GSK3β at tyrosine 216 (Y216). GSK3β activity is also regulated by phosphorylation at serine residue 9 (Ser9) by the receptor tyrosine kinase (RTK)-PI3K-AKT pathway. Antipsychotic drugs, the mood stabilizer lithium, and drugs inducing psychosis alter GSK3β activity indirectly by different mechanisms. DISC1 also interacts with other proteins, including NDEL1, Lis-1, PDE4B, FEZ1, and kinesin. (PI3K, phosphoinositide-3 kinase; GSK3β, glycogen synthase kinase 3β; NDEL1, NudElike 1; Lis-1, Lissencephaly-1; PDE4B, phosphodiesterase 4B; FEZ-1, fasciculation and elongation protein zeta 1.)