DISC1-dependent switch from progenitor proliferation to migration in the developing cortex

摘要

Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood^–. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons. Unphosphorylated DISC1 regulates canonical Wnt signaling via an interaction with GSK3β, whereas specific phosphorylation at Serine 710 (S710) triggers the recruitment of Bardet-Biedl-Syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, while DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, while a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and suggest that phosphorylation of this protein at S710 activates a key developmental switch.