TY - JOUR
T1 - The exon junction complex component Magoh controls brain size by regulating neural stem cell division
AU - Silver, Debra L.
AU - Watkins-Chow, Dawn E.
AU - Schreck, Karisa C.
AU - Pierfelice, Tarran J.
AU - Larson, Denise M.
AU - Burnetti, Anthony J.
AU - Liaw, Hung Jiun
AU - Myung, Kyungjae
AU - Walsh, Christopher A.
AU - Gaiano, Nicholas
AU - Pavan, William J.
N1 - Funding Information:
For advice, we thank Pavan laboratory members, including L. Baxter for reading the manuscript. For technical assistance, we thank A. Incao (mouse husbandry); G. Elliot and A. Chen (mouse transgenics); A. Dutra, E. Pak and S. Witchovitch (metaphase, SKY, microscopy assistance); S. Anderson and M. Kirby (FACS analysis); B. Bhorate (microarray statistics); M. Bryant (pathology analysis); Harvard Partners Center for Genetics and Genomics (candidate gene sequencing); and J. Fekecs and D. Leja (assistance with figures). This research was funded in part by an National Institute of General Medical Sciences PRAT fellowship and K99/R00 Pathway to Independence Award (to D.L.S.), by the Intramural Research program of NIH/NHGRI (to W.J.P., K.M.) and by the NIH/NHGRI (to N.G.). C.A.W. is an Investigator of the Howard Hughes Medical Institute.
PY - 2010/5
Y1 - 2010/5
N2 - Brain structure and size require precise division of neural stem cells (NSCs), which self-renew and generate intermediate neural progenitors (INPs) and neurons. The factors that regulate NSCs remain poorly understood, and mechanistic explanations of how aberrant NSC division causes the reduced brain size seen in microcephaly are lacking. Here we show that Magoh, a component of the exon junction complex (EJC) that binds RNA, controls mouse cerebral cortical size by regulating NSC division. Magoh haploinsufficiency causes microcephaly because of INP depletion and neuronal apoptosis. Defective mitosis underlies these phenotypes, as depletion of EJC components disrupts mitotic spindle orientation and integrity, chromosome number and genomic stability. In utero rescue experiments showed that a key function of Magoh is to control levels of the microcephaly-associated protein Lis1 during neurogenesis. Our results uncover requirements for the EJC in brain development, NSC maintenance and mitosis, thereby implicating this complex in the pathogenesis of microcephaly.
AB - Brain structure and size require precise division of neural stem cells (NSCs), which self-renew and generate intermediate neural progenitors (INPs) and neurons. The factors that regulate NSCs remain poorly understood, and mechanistic explanations of how aberrant NSC division causes the reduced brain size seen in microcephaly are lacking. Here we show that Magoh, a component of the exon junction complex (EJC) that binds RNA, controls mouse cerebral cortical size by regulating NSC division. Magoh haploinsufficiency causes microcephaly because of INP depletion and neuronal apoptosis. Defective mitosis underlies these phenotypes, as depletion of EJC components disrupts mitotic spindle orientation and integrity, chromosome number and genomic stability. In utero rescue experiments showed that a key function of Magoh is to control levels of the microcephaly-associated protein Lis1 during neurogenesis. Our results uncover requirements for the EJC in brain development, NSC maintenance and mitosis, thereby implicating this complex in the pathogenesis of microcephaly.
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U2 - 10.1038/nn.2527
DO - 10.1038/nn.2527
M3 - Article
C2 - 20364144
AN - SCOPUS:77951667779
VL - 13
SP - 551
EP - 558
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 5
ER -