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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
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1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
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Age Factors
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Animals
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Animals, Newborn
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Apoptosis / genetics
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Brain / embryology
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Brain / growth & development
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Brain / pathology*
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Bromodeoxyuridine / metabolism
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Cell Differentiation / genetics
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Cell Division / genetics*
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DNA Mutational Analysis
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Embryo, Mammalian
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Eye Proteins / genetics
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Eye Proteins / metabolism
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Gene Expression Profiling / methods
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Gene Expression Regulation, Developmental / genetics
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Genotype
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Green Fluorescent Proteins / genetics
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HeLa Cells
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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In Situ Nick-End Labeling / methods
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microcephaly / genetics
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Microcephaly / pathology*
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Microcephaly / physiopathology
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mutation / genetics
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurogenesis / genetics
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Neurons / pathology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis / methods
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Organ Size / genetics
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PAX6 Transcription Factor
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Paired Box Transcription Factors / genetics
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Paired Box Transcription Factors / metabolism
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RNA Interference / physiology
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RNA, Messenger / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Stem Cells / physiology*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / metabolism
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Transfection
Substances
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Eomes protein, mouse
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Eye Proteins
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Homeodomain Proteins
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Magoh protein, mouse
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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PAX6 Transcription Factor
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PAX6 protein, human
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Paired Box Transcription Factors
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Pax6 protein, mouse
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RNA, Messenger
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Repressor Proteins
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T-Box Domain Proteins
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Green Fluorescent Proteins
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1-Alkyl-2-acetylglycerophosphocholine Esterase
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Pafah1b1 protein, mouse
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Bromodeoxyuridine