Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly.
The exon junction complex (EJC) is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis and microcephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employ mouse 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 components. We further demonstrate all 3 mutants exhibit defective splicing of RNA regulatory proteins, implying an EJC dependent RNA regulatory network that fine-tunes gene expression. Finally, we show that genetic ablation of one downstream pathway, p53, significantly rescues microcephaly of all 3 EJC mutants. This implicates p53 activation as a major 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.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Hanqian
H
Mao
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
John J
JJ
McMahon
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Yi-Hsuan
0000-0003-2107-4300
YH
Tsai
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Zefeng
Z
Wang
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, United States of America.|Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, United States of America.|Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina, United States of America.|Duke Institute for Brain Sciences, Duke University, Durham, North Carolina, United States of America.
Debra L
DL
Silver
D000818:Animals; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020543:Proteome / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
C491493:Magoh protein, mouse; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D020543:Proteome; C586565:RBM8A protein, mouse; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D039601:Eukaryotic Initiation Factor-4A