title: 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 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Koko
authors.initials: K
authors.lastname: Ishizuka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Oh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanki
authors.forename: Saurav
authors.initials: S
authors.lastname: Seshadri
authors.forename: Jon F
authors.initials: JF
authors.lastname: Robinson
authors.forename: Hannah
authors.initials: H
authors.lastname: Murdoch
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Dunlop
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kubo
authors.forename: Keiko
authors.initials: K
authors.lastname: Furukori
authors.forename: Beverly
authors.initials: B
authors.lastname: Huang
authors.forename: Mariela
authors.initials: M
authors.lastname: Zeledon
authors.forename: Akiko
authors.initials: A
authors.lastname: Hayashi-Takagi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakajima
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
mesh_terms: D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D002522:Chlorocebus aethiops; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C506280:Bbs1 protein, mouse; C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3