Publication Date:
2011-04-08
Description:
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 GSK3beta, 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088774/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088774/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- DK-072301/DK/NIDDK NIH HHS/ -- DK-075972/DK/NIDDK NIH HHS/ -- G0600765/Medical Research Council/United Kingdom -- HD-04260/HD/NICHD NIH HHS/ -- MH-069853/MH/NIMH NIH HHS/ -- MH-084018/MH/NIMH NIH HHS/ -- MH-085226/MH/NIMH NIH HHS/ -- MH-088753/MH/NIMH NIH HHS/ -- MH-091230/MH/NIMH NIH HHS/ -- R01 DK072301/DK/NIDDK NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 DK075972-06/DK/NIDDK NIH HHS/ -- R01 HD042601/HD/NICHD NIH HHS/ -- R01 HD042601-10/HD/NICHD NIH HHS/ -- R01 MH091230/MH/NIMH NIH HHS/ -- R01 MH092443/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 5;473(7345):92-6. doi: 10.1038/nature09859. Epub 2011 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21471969" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
COS Cells
;
Cell Movement/genetics
;
Cell Proliferation
;
Cercopithecus aethiops
;
Cerebral Cortex/cytology/*embryology/physiology
;
Gene Knockdown Techniques
;
Glycogen Synthase Kinase 3/metabolism
;
HEK293 Cells
;
Humans
;
Mice
;
Microtubule-Associated Proteins/genetics/metabolism
;
*Nerve Tissue Proteins/genetics/metabolism
;
Neurons/*cytology/metabolism/*physiology
;
PC12 Cells
;
Phosphorylation
;
Protein Binding
;
Rats
;
Signal Transduction
;
Stem Cells/*cytology
;
Wnt Proteins/metabolism
;
beta Catenin/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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