The gene encoding DISC1 (disrupted in schizophrenia 1) is a susceptibility factor for various mental disorders. DISC1 interacts with and inhibits the kinase GSK-3β to enable Wnt activation of β-catenin–mediated gene transcription and proliferation, a process that is required in the initial stages of the development of the cerebral cortex. Proliferating progenitor cells must exit the cell cycle and migrate to the correct locations in the cerebral cortex. Intriguingly, DISC1 also binds to centrosomal proteins, such as Bardet-Biedl syndrome (BBS) 1 and BBS4, and a role for BBS4 in promoting neuronal migration has been suggested. Ishizuka et al. postulated that phosphorylation could alter the affinity of DISC1 for its binding partners and enable DISC1 to act as the switch between proliferation and migration in cortical neurons. Mass spectrometry analysis and in vitro assays indicated that human DISC1 was phosphorylated at Ser713 by protein kinase A (PKA) or the kinase CDK5 (the analogous residue in mouse DISC1 is Ser710). A form of mouse DISC1 that could not be phosphorylated at Ser710 showed decreased interaction with BBS1 and BBS4 compared with wild-type DISC1, whereas a form that mimicked constitutive phosphorylation showed increased interaction. Transfection of cortical neurons with the phosphomimetic DISC1 mutant increased the localization of BBS1 to the centrosome compared with those transfected with wild-type or the nonphosphorylatable mutant. In contrast, the decrease in β-catenin transcriptional activity elicited by RNA interference (RNAi) directed against DISC1 in transfected cells or mouse embryos was rescued by expression of wild-type DISC1 or the nonphosphorylatable DISC1 mutant, but not the phosphomimetic mutant. In mouse cortex, DISC1 phosphorylation at Ser710 was low, and interaction with GSK-3β was most prominent at E14, when progenitor cells are actively proliferating, whereas at E18, when postmitotic neurons are migrating, DISC1 phosphorylation was prominent, association with GSK-3β was low, and interaction with BBS1 was enhanced. Accordingly, proliferation defects in E14 embryos caused by RNAi against DISC1 were rescued by expression of the nonphosphorylatable DISC1 mutant, whereas DISC1 RNAi-triggered delays in neuronal migration in E18 embryos were rescued by expression of the phosphomimetic DISC1 mutant. Moreover, mice lacking BBS1 or those expressing a dominant-negative form of CDK5 also showed deficits in neuronal migration, which, in the latter case, was rescued only by the phosphomimetic form of DISC1. Thus, a developmentally timed phosphorylation event appears to reduce the binding of DISC1 to GSK-3β to attenuate proliferation and enable it to recruit to the centrosome proteins involved in neuronal migration.
K. Ishizuka, A. Kamiya, E. C. Oh, H. Kanki, S. Seshadri, J. F. Robinson, H. Murdoch, A. J. Dunlop, K.-i. Kubo, K. Furukori, B. Huang, M. Zeledon, A. Hayashi-Takagi, H. Okano, K. Nakajima, M. D. Houslay, N. Katsanis, A. Sawa, DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature 473, 92–96 (2011). [PubMed]