title: Neuronal Splicing Regulator RBFOX3 (NeuN) Regulates Adult Hippocampal Neurogenesis and Synaptogenesis.
abstract: Dysfunction of RBFOX3 has been identified in neurodevelopmental disorders such as autism spectrum disorder, cognitive impairments and epilepsy and a causal relationship with these diseases has been previously demonstrated with Rbfox3 homozygous knockout mice. Despite the importance of RBFOX3 during neurodevelopment, the function of RBFOX3 regarding neurogenesis and synaptogenesis remains unclear. To address this critical question, we profiled the developmental expression pattern of Rbfox3 in the brain of wild-type mice and analyzed brain volume, disease-relevant behaviors, neurogenesis, synaptic plasticity, and synaptogenesis in Rbfox3 homozygous knockout mice and their corresponding wild-type counterparts. Here we report that expression of Rbfox3 differs developmentally for distinct brain regions. Moreover, Rbfox3 homozygous knockout mice exhibited cold hyperalgesia and impaired cognitive abilities. Focusing on hippocampal phenotypes, we found Rbfox3 homozygous knockout mice displayed deficits in neurogenesis, which was correlated with cognitive impairments. Furthermore, RBFOX3 regulates the exons of genes with synapse-related function. Synaptic plasticity and density, which are related to cognitive behaviors, were altered in the hippocampal dentate gyrus of Rbfox3 homozygous knockout mice; synaptic plasticity decreased and the density of synapses increased. Taken together, our results demonstrate the important role of RBFOX3 during neural development and maturation. In addition, abnormalities in synaptic structure and function occur in Rbfox3 homozygous knockout mice. Our findings may offer mechanistic explanations for human brain diseases associated with dysfunctional RBFOX3.
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Sian
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Han-Ying
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: De-Fong
authors.initials: DF
authors.lastname: Huang
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Meng-Ying
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Hsuan
authors.initials: CH
authors.lastname: Chou
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: I-Ju
authors.initials: IJ
authors.lastname: Wu
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Guo-Jen
authors.initials: GJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan.|Clinical Center for Neuroscience and Behavior, National Taiwan University Hospital, Taipei, Taiwan.|Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Susan Shur-Fen
authors.initials: SS
authors.lastname: Gau
authors.affiliation: Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.|Clinical Center for Neuroscience and Behavior, National Taiwan University Hospital, Taipei, Taiwan.|Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan.|Ph.D. Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, Taiwan.|Neurodevelopment Club in Taiwan, Taipei, Taiwan.
authors.forename: Hsien-Sung
authors.identifier: http://orcid.org/0000-0003-2657-3635
authors.initials: HS
authors.lastname: Huang
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000254:growth & development*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D065886:Neurodevelopmental Disorders / Q000235:genetics* / Q000473:pathology; D055495:Neurogenesis; D009473:Neuronal Plasticity; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins