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

Koko Ishizuka, Atsushi Kamiya, Edwin Oh, Hiroaki Kanki, Saurav Seshadri, Jon Robinson, Hannah Murdoch, Allan Dunlop, Ken-ichiro Kubo, Keiko Furukori, Beverly Huang, Mariela Zeledon, Ariko Hayashi-Takagi, Hideyuki Okano, Kazunori Nakajima, Miles Houslay, Nicholas Katsanis, Akira Sawa

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151 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)92-96
Number of pages5
JournalNature
Volume473
Issue number7345
Early online date6 Apr 2011
DOIs
Publication statusPublished - 5 May 2011

Keywords

  • DISC1
  • phosphorylation
  • corticogenesis
  • GSK3 beta
  • Wnt
  • Bardet-Biedl syndrome

Cite this

Ishizuka, K., Kamiya, A., Oh, E., Kanki, H., Seshadri, S., Robinson, J., Murdoch, H., Dunlop, A., Kubo, K., Furukori, K., Huang, B., Zeledon, M., Hayashi-Takagi, A., Okano, H., Nakajima, K., Houslay, M., Katsanis, N., & Sawa, A. (2011). DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature, 473(7345), 92-96. https://doi.org/10.1038/nature09859