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

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Date
2010-05
Authors
Silver, Debra L
Watkins-Chow, Dawn E
Schreck, Karisa C
Pierfelice, Tarran J
Larson, Denise M
Burnetti, Anthony J
Liaw, Hung-Jiun
Myung, Kyungjae
Walsh, Christopher A
Gaiano, Nicholas
Pavan, William J
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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.
Type
Journal article
Subject
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
Permalink
https://hdl.handle.net/10161/14117
Published Version (Please cite this version)
10.1038/nn.2527
Publication Info
Silver, 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.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Silver

Debra Lynn Silver

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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