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

• Published in: Nature (London) Vol. 473; no. 7345; pp. 92 - 96
• Main Authors: Ishizuka, Koko, Kamiya, Atsushi, Oh, Edwin C., Kanki, Hiroaki, Seshadri, Saurav, Robinson, Jon F., Murdoch, Hannah, Dunlop, Allan J., Kubo, Ken-ichiro, Furukori, Keiko, Huang, Beverly, Zeledon, Mariela, Hayashi-Takagi, Akiko, Okano, Hideyuki, Nakajima, Kazunori, Houslay, Miles D., Katsanis, Nicholas, Sawa, Akira
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.05.2011; Nature Publishing Group
• Subjects: 631/378/2571; 631/378/2620/1369; 631/80/84; 692/699/476; Amino acids; Animals; Autism; beta Catenin - metabolism; Biological and medical sciences; Cell Movement - genetics; Cell Proliferation; Cercopithecus aethiops; Cerebral cortex; Cerebral Cortex - cytology; Cerebral Cortex - embryology; Cerebral Cortex - physiology; COS Cells; Fundamental and applied biological sciences. Psychology; Gene Knockdown Techniques; Genetic aspects; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HEK293 Cells; Humanities and Social Sciences; Humans; letter; Mass spectrometry; Mental disorders; Mice; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons - cytology; Neurons - metabolism; Neurons - physiology; PC12 Cells; Phosphorylation; Physiological aspects; Plasmids; Protein Binding; Proteins; Rats; Risk factors; Rodents; Schizophrenia; Science; Science (multidisciplinary); Signal Transduction; Stem Cells - cytology; Vertebrates: nervous system and sense organs; Wnt Proteins - metabolism; United States; Cell proliferation; Phosphorylation; Enzyme; Transferases; Serine; Rodentia; Precursor cell; Protein; Recruitment; Cell motility; Vertebrata; Sensitivity; Mammalia; Neuron; Mouse; Glycogen synthase kinase-3β; Animal; Development; Regulatory sequence
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09859

DISC1 protein as a developmental switch The schizophrenia susceptibility factor DISC1 is highly enriched in the developing cerebral cortex, suggesting that it may have an important role during this time period. Sawa and colleagues find a specific phosphorylation site that acts as a molecular switch to transform a dividing progenitor into a postmitotic, migrating neuron. In each phosphorylation state, DISC1 interacts primarily with a distinct signalling pathway. It may therefore perform a dual role in corticogenesis, dependent on its phosphorylation status. Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood 1 , 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.