Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly
Publication Date
September 12, 2016
Journal
PLOS Genetics
Authors
Hanqian Mao, John J. Mc Mahon, Yi Hsuan Tsai, Zefeng Wang, et al
Volume
12
Issue
9
Pages
e1006282
DOI
https://dx.plos.org/10.1371/journal.pgen.1006282
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1006282
Scopus
84990220405
Mendeley
http://www.mendeley.com/research/haploinsufficiency-core-exon-junction-complex-components-disrupts-embryonic-neurogenesis-causes-p53m
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Mendeley | Further Information

{"title"=>"Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly", "type"=>"journal", "authors"=>[{"first_name"=>"Hanqian", "last_name"=>"Mao", "scopus_author_id"=>"26660161600"}, {"first_name"=>"John J.", "last_name"=>"McMahon", "scopus_author_id"=>"37561473400"}, {"first_name"=>"Yi Hsuan", "last_name"=>"Tsai", "scopus_author_id"=>"57189729330"}, {"first_name"=>"Zefeng", "last_name"=>"Wang", "scopus_author_id"=>"7410048449"}, {"first_name"=>"Debra L.", "last_name"=>"Silver", "scopus_author_id"=>"7202150881"}], "year"=>2016, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"84990220405", "doi"=>"10.1371/journal.pgen.1006282", "pui"=>"612628532", "pmid"=>"27618312", "scopus"=>"2-s2.0-84990220405", "issn"=>"15537404"}, "id"=>"954d4604-86f5-3724-afe6-16281f845819", "abstract"=>"The exon junction complex (EJC) is an RNA binding complex comprised of the core compo- nents Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodeve- lopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis andmicrocephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employmouse genetics, transcriptomic and proteomic analyses to demonstrate that haploinsufficiency for each of the 3 core EJC components causes microcephaly via converging regulation of p53 signaling. Using a new conditional allele, we first show that Eif4a3 haploinsufficiency phenocopies aberrant neurogenesis and microcephaly of Magoh and Rbm8a mutant mice. Transcriptomic and proteomic analyses of embryonic brains at the onset of neurogenesis identifies common pathways altered in each of the 3 EJC mutants, including ribosome, proteasome, and p53 signaling compo- nents.We further demonstrate all 3 mutants exhibit defective splicing of RNA regulatory proteins, implying an EJC dependent RNA regulatory network that fine-tunes gene expres- sion. Finally, we show that genetic ablation of one downstream pathway, p53, significantly rescues microcephaly of all 3 EJC mutants. This implicates p53 activation as amajor node of neurodevelopmental pathogenesis following EJC impairment. Altogether our study reveals new mechanisms to help explain how EJC mutations influence neurogenesis and underlie neurodevelopmental disease.", "link"=>"http://www.mendeley.com/research/haploinsufficiency-core-exon-junction-complex-components-disrupts-embryonic-neurogenesis-causes-p53m", "reader_count"=>27, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Other"=>3, "Student > Bachelor"=>3, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Other"=>3, "Student > Bachelor"=>3, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>10, "Agricultural and Biological Sciences"=>9, "Neuroscience"=>4, "Computer Science"=>1, "Environmental Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Neuroscience"=>{"Neuroscience"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}, "Unspecified"=>{"Unspecified"=>1}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1}, "group_count"=>0}

Scopus | Further Information

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