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The exon junction complex component Magoh controls brain size by regulating neural stem cell division

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Abstract

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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Figure 1: Mutation of Magoh causes microcephaly and reduced body size.
Figure 2: E18.5 MagohMos2/+ brains contain disorganized layers and fewer neurons.
Figure 3: Magoh is required for proper numbers of INPs but not NSCs.
Figure 4: Magoh is required to prevent premature neuronal differentiation and apoptosis.
Figure 5: Magoh and core EJC components regulate the mitotic spindle, ploidy, mitosis and genomic stability.
Figure 6: Magoh acts upstream of the microcephaly-associated protein Lis1 to regulate neurogenesis.

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Change history

  • 19 April 2010

    In the version of this article initially published online, the last sentence of the sixth paragraph in the Discussion section read “Future studies will reveal, for example, whether any of the genes altered in our microarray or proteomics experiments are also essential targets of MAGOH.” MAGOH has been corrected to Magoh, denoting the mouse gene. Also, the second sentence of the last paragraph in the Discussion section initially read “Of note, Magoh is found within a 55-gene deletion on chromosome 1p32.3 that is associated with mental retardation and abnormalities in brain size31.” Magoh has been corrected to MAGOH, denoting the human gene. These errors have been corrected in the print, HTML and PDF versions of the article.

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Acknowledgements

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.

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Contributions

D.L.S. designed the study, performed all experiments except where noted otherwise and wrote the paper. D.E.W.-C. performed all mRNA analyses and assisted with quantitative analyses. K.C.S. and T.J.P. performed all in utero electroporations and dissections of electroporated brains. D.M.L. performed staining of E18.5 markers. A.J.B. assisted with HeLa cell analyses and quantification of NSCs and INPs. H.L. performed RPE cell analyses. D.L.S., W.J.P., C.A.W., N.G. and K.M. were involved in research design, and all authors were involved in data analysis. D.L.S. and W.J.P. prepared the manuscript. All authors have agreed to the content in the manuscript, including the data as presented.

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Correspondence to William J Pavan.

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Supplementary Figures 1–9 and Supplementary Tables 1–3 (PDF 12447 kb)

Supplementary Data

Serum chemistries, hematology, and organ weights of control and mutant animals (XLS 83 kb)

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Silver, D., Watkins-Chow, D., Schreck, K. et al. The exon junction complex component Magoh controls brain size by regulating neural stem cell division. Nat Neurosci 13, 551–558 (2010). https://doi.org/10.1038/nn.2527

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