The exon junction complex component Magoh controls brain size by regulating neural stem cell division
Copyright policy )The exon junction complex component Magoh controls brain size by regulating neural stem cell division
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.
- Harvard Medical School United States
- Duke University United States
- John Hopkins University School of Medecine United States
- UNIST (Ulsan National Institute of Science and Technology) Korea (Republic of)
- National Institute of Health (NIH/NICHD) United States
571, PAX6 Transcription Factor, Genotype, Neurogenesis, Messenger, DNA Mutational Analysis, Green Fluorescent Proteins, Nerve Tissue Proteins, Apoptosis, Inbred C57BL, Transfection, Transgenic, Article, Mice, In Situ Nick-End Labeling, Paired Box Transcription Factors, Animals, Humans, Developmental, Eye Proteins, Oligonucleotide Array Sequence Analysis, Neurons, Homeodomain Proteins, Mammalian, Stem Cells, Gene Expression Profiling, Age Factors, Nuclear Proteins, Brain, Gene Expression Regulation, Developmental, Cell Differentiation, Organ Size, Newborn, Embryo, Mammalian, Repressor Proteins, Gene Expression Regulation, Animals, Newborn, Bromodeoxyuridine, Embryo, Mutation, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Microcephaly, RNA, RNA Interference, T-Box Domain Proteins, Microtubule-Associated Proteins, Cell Division, HeLa Cells
571, PAX6 Transcription Factor, Genotype, Neurogenesis, Messenger, DNA Mutational Analysis, Green Fluorescent Proteins, Nerve Tissue Proteins, Apoptosis, Inbred C57BL, Transfection, Transgenic, Article, Mice, In Situ Nick-End Labeling, Paired Box Transcription Factors, Animals, Humans, Developmental, Eye Proteins, Oligonucleotide Array Sequence Analysis, Neurons, Homeodomain Proteins, Mammalian, Stem Cells, Gene Expression Profiling, Age Factors, Nuclear Proteins, Brain, Gene Expression Regulation, Developmental, Cell Differentiation, Organ Size, Newborn, Embryo, Mammalian, Repressor Proteins, Gene Expression Regulation, Animals, Newborn, Bromodeoxyuridine, Embryo, Mutation, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Microcephaly, RNA, RNA Interference, T-Box Domain Proteins, Microtubule-Associated Proteins, Cell Division, HeLa Cells
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