title: Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes.
abstract: Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate the function of cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that Rbfox1 bound predominantly to introns in nascent RNA, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and Rbfox1 and miRNA binding sites overlapped significantly. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease.
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ji-Ann
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Damianov
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Chia-Ho
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Fontes
authors.affiliation: Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Neelroop N
authors.initials: NN
authors.lastname: Parikshak
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Anderson
authors.affiliation: Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Black
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: kcmartin@mednet.ucla.edu.
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Martin
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004964:Estriol / Q000031:analogs & derivatives* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C465036:Rbfox1 protein, mouse; C009341:estriol succinate; D004964:Estriol