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

Abstract

Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood1,2,3,4,5,6,7,8,9,10. 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.

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Figure 1: Phosphorylation of DISC1 at S710 selectively increases binding of DISC1 with BBS proteins, resulting in enhanced BBS1 accumulation at the centrosome.
Figure 2: Non-phosphorylated DISC1 at S710 activates β-catenin signalling via its interaction with GSK3β.
Figure 3: Binding affinity of DISC1–GSK3β to DISC1–BBS1 depends on developmental stage: roles of BBS1 in corticogenesis.
Figure 4: Suppression of DISC1 leads to phospho-dependent defects in cell proliferation and neuronal migration: implication of CDK5.

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Acknowledgements

We thank Y. Y. Lema for preparing figures and organizing the manuscript and P. Talalay for critical reading of this manuscript. We appreciate J. M. Gerdes, A. K. Mustafa, N. Shahani, T. Boronina, D. Chen and R. N. Cole for scientific discussions and technical support. We thank T. Tomoda, N. Sugiyama, M. Hasegawa, Q. Lu, E. S. Anton and A. Chenn for providing us with constructs. This work was supported by USPHS grants of MH-084018 Silvo O. Conte center (A.S.), MH-069853 (A.S.), MH-085226 (A.S.), MH-088753 (A.S.), MH-091230 (A.K.), HD-04260 (N.K.), DK-072301 (N.K.), and DK-075972 (N.K.); grants from Stanley and RUSK foundations and from Maryland Stem Cell Research Fund (A.S.); grants from NARSAD and S-R foundations (A.S. and A.K.); grants from the Macular Vision Research Foundation and the Foundation for Fighting Blindness as well as the Distinguished George W. Brumley Professorship (N.K.); a grant from Health Labor Sciences (K.-i.K.); grants from Strategic Research Program for Brain Sciences (K.N.), MEXT (K.N.), Takeda (K.N.) and PMAC-PSJ (K.N.); Fight for Sight Postdoctoral Fellowship (E.O.); grant from the Medical Research Council, UK (G0600765; M.D.H.).

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K.I. and A.S. conceived the general ideas for this study. K.I., A.K., E.C.O., N.K. and A.S. designed experiments. K.I., A.K., E.C.O. and J.F.R. performed the experiments and data analysis with assistance from H.K., S.S., H.M., A.J.D., K.-i.K., K.F., B.H., M.Z., A.H.-T., H.O., K.N. and M.D.H.; K.I., A.K., E.C.O., M.D.H., N.K. and A.S. wrote the manuscript.

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Correspondence to Nicholas Katsanis or Akira Sawa.

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Ishizuka, K., Kamiya, A., Oh, E. et al. DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature 473, 92–96 (2011). https://doi.org/10.1038/nature09859

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