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

Ishizuka, Koko and Kamiya, Atsushi and Oh, Edwin and Kanki, Hiroaki and Seshadri, Saurav and Robinson, Jon and Murdoch, Hannah and Dunlop, Allan and Kubo, Ken-ichiro and Furukori, Keiko and Huang, Beverly and Zeledon, Mariela and Hayashi-Takagi, Ariko and Okano, Hideyuki and Nakajima, Kazunori and Houslay, Miles and Katsanis, Nicholas and Sawa, Akira (2011) DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature, 473 (7345). pp. 92-96. ISSN 0028-0836

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Abstract

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 in mice. Unphosphorylated DISC1 regulates canonical Wnt signalling 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, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at S710 activates a key developmental switch.