The exon junction complex component Magoh controls brain size by regulating neural stem cell division.
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 articleSubject
1-Alkyl-2-acetylglycerophosphocholine EsteraseAge 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/10161/14117Published Version (Please cite this version)
10.1038/nn.2527Publication 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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Show full item recordScholars@Duke
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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