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

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2010-05

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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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1-Alkyl-2-acetylglycerophosphocholine Esterase, Age Factors, Animals, Animals, Newborn, Apoptosis, Brain, Bromodeoxyuridine, Cell Differentiation, Cell Division, DNA Mutational Analysis, Embryo, Mammalian, Eye Proteins, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genotype, Green Fluorescent Proteins, HeLa Cells, Homeodomain Proteins, Humans, In Situ Nick-End Labeling, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microcephaly, Microtubule-Associated Proteins, Mutation, Nerve Tissue Proteins, Neurogenesis, Neurons, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Organ Size, PAX6 Transcription Factor, Paired Box Transcription Factors, RNA Interference, RNA, Messenger, Repressor Proteins, Stem Cells, T-Box Domain Proteins, Transfection

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https://hdl.handle.net/10161/14117

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10.1038/nn.2527

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Silver, Debra L, Dawn E Watkins-Chow, Karisa C Schreck, Tarran J Pierfelice, Denise M Larson, Anthony J Burnetti, Hung-Jiun Liaw, Kyungjae Myung, et al. (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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Silver

Debra Lynn Silver

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 pathologies and brain evolution. We study neural progenitors, essential cells which generate neurons and are the root of brain development. We are guided by the premise that the same mechanisms at play during normal development were co-opted during evolution and when dysregulated, can cause neurodevelopmental disease.

My research program employs a multifaceted strategy to bridge developmental neurobiology, RNA biology, and evolution. 1) We investigate how cell fates are specified, by studying how progenitor divisions influence development and disease.  2) We study diverse layers of post-transcriptional regulation in neural progenitors. We investigate RNA binding proteins implicated in development and neurological disease. Using live imaging, we also investigate how sub-cellular control of mRNA localization and translation influences neural progenitors. 3) A parallel research focus is to understand how human-specific genetic changes influence species-specific brain development. Our goal is to integrate our efforts across these three major lines of research to understand the intricacies controlling brain development.

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