The exon junction complex component Magoh controls brain size by regulating neural stem cell division.
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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.
DNA Mutational Analysis
Gene Expression Profiling
Gene Expression Regulation, Developmental
Green Fluorescent Proteins
In Situ Nick-End Labeling
Mice, Inbred C57BL
Nerve Tissue Proteins
Oligonucleotide Array Sequence Analysis
PAX6 Transcription Factor
Paired Box Transcription Factors
T-Box Domain Proteins
Published Version (Please cite this version)10.1038/nn.2527
Publication InfoSilver, Debra L; Watkins-Chow, Dawn E; Schreck, Karisa C; Pierfelice, Tarran J; Larson, Denise M; Burnetti, Anthony J; ... Pavan, William J (2010). The exon junction complex component Magoh controls brain size by regulating neural stem cell division. Nat Neurosci, 13(5). pp. 551-558. 10.1038/nn.2527. Retrieved from https://hdl.handle.net/10161/14117.
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Associate Professor of Molecular Genetics and Microbiology
How is the brain assembled and sculpted during embryonic development? Addressing this question has enormous implications for understanding neurodevelopmental disorders affecting brain size and function. In evolutionary terms, our newest brain structure is the cerebral cortex, which drives higher cognitive capacities. The overall mission of my research lab is to elucidate genetic and cellular mechanisms controlling cortical development and contributing to neurodevelopmental patho
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