title: A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors.
abstract: BACKGROUND
  Nonsense mediated mRNA decay (NMD) is an RNA surveillance mechanism that controls RNA stability and ensures the speedy degradation of erroneous and unnecessary transcripts. This mechanism depends on several core factors in the exon junction complex (EJC), eIF4A3, RBM8a, Magoh, and BTZ, as well as peripheral factors to distinguish premature stop codons (PTCs) from normal stop codons in transcripts. Recently, emerging evidence has indicated that NMD factors are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the mechanism in which these factors control embryonic brain development is not clear.
  
  
  RESULTS
  We found that RBM8a is critical for proliferation and differentiation in cortical neural progenitor cells (NPCs). RBM8a is highly expressed in the subventricular zone (SVZ) of the early embryonic cortex, suggesting that RBM8a may play a role in regulating NPCs. RBM8a overexpression stimulates embryonic NPC proliferation and suppresses neuronal differentiation. Conversely, knockdown of RBM8a in the neocortex reduces NPC proliferation and promotes premature neuronal differentiation. Moreover, overexpression of RBM8a suppresses cell cycle exit and keeps cortical NPCs in a proliferative state. To uncover the underlying mechanisms of this phenotype, genome-wide RNAseq was used to identify potential downstream genes of RBM8a in the brain, which have been implicated in autism and neurodevelopmental disorders. Interestingly, autism and schizophrenia risk genes are highly represented in downstream transcripts of RBM8a. In addition, RBM8a regulates multiple alternative splicing genes and NMD targets that are implicated in ASD. Taken together, this data suggests a novel role of RBM8a in the regulation of neurodevelopment.
  
  
  CONCLUSIONS
  Our studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, 530021, China. danvor0922@hotmail.com.|Department of Geriatrics, The 303 Hospital of Chinese People's Liberation Army, Nanning, Guangxi Province, 530021, China. danvor0922@hotmail.com.|Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA. danvor0922@hotmail.com.
authors.forename: Donghua
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA. cpm186@psu.edu.
authors.forename: Colleen
authors.initials: C
authors.lastname: McSweeney
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA. azs13@psu.edu.
authors.forename: Aswathy
authors.initials: A
authors.lastname: Sebastian
authors.affiliation: Department of Microbiology & Molecular Genetics School of Medicine, University of California, Irvine, CA, 92697, USA. derrick.reynolds1@gmail.com.
authors.forename: Derrick James
authors.initials: DJ
authors.lastname: Reynolds
authors.affiliation: Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA. fud10@psu.edu.
authors.forename: Fengping
authors.initials: F
authors.lastname: Dong
authors.affiliation: Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA. yxz167@psu.edu.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA. dxd50@psu.edu.|Department of Emergency, Guangxi Zhuang Autonomous Region People's Hospital, Nanning, Guangxi Province, 530021, China. dxd50@psu.edu.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Deng
authors.affiliation: Department of Neurology, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, 200127, China. w100yg@gmail.com.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA. llbio@126.com.|Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, 410073, China. llbio@126.com.
authors.forename: Long
authors.initials: L
authors.lastname: Liu
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, 20892, USA. jun.zhu@nih.gov.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, 20892, USA. jizhong.zou@nih.gov.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Microbiology & Molecular Genetics School of Medicine, University of California, Irvine, CA, 92697, USA. yongshes@uci.edu.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA. iua1@psu.edu.
authors.forename: Istvan
authors.initials: I
authors.lastname: Albert
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, 530021, China. yzm1@psu.edu.|Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA. yzm1@psu.edu.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Mao
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014162:Transfection
chemical_list: C406243:RBM8A protein, human; C586565:RBM8A protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins