title: Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis.
abstract: Alternative splicing plays important regulatory roles during periods of physiological change. During development, a large number of genes coordinately express protein isoform transitions regulated by alternative splicing; however, the mechanisms that coordinate splicing and the functional integration of the resultant tissue-specific protein isoforms are typically unknown. Here we show that the conserved Rbfox2 RNA binding protein regulates 30% of the splicing transitions observed during myogenesis and is required for the specific step of myoblast fusion. Integration of Rbfox2-dependent splicing outcomes from RNA-seq with Rbfox2 iCLIP data identified Mef2d and Rock2 as Rbfox2 splicing targets. Restored activities of Mef2d and Rock2 rescued myoblast fusion in Rbfox2-depleted cultures, demonstrating functional cooperation of protein isoforms generated by coordinated alterative splicing. The results demonstrate that coordinated alternative splicing by a single RNA binding protein modulates transcription (Mef2d) and cell signaling (Rock2) programs to drive tissue-specific functions (cell fusion) to promote a developmental transition.
authors.affiliation: Departments of Pathology and Immunology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Departments of Molecular and Cellular Biology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.|Departments of Dan L. Duncan Cancer Center, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.affiliation: The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Bland
authors.affiliation: Departments of Pathology and Immunology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
authors.forename: Auinash
authors.initials: A
authors.lastname: Kalsotra
authors.affiliation: Departments of Pathology and Immunology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Scavuzzo
authors.affiliation: University of Ljubljana, Faculty of Computer and Information Science, Trẑaŝka cesta 25, SI-1000 Ljubljana.
authors.forename: Tomaz
authors.initials: T
authors.lastname: Curk
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.affiliation: Departments of Molecular and Cellular Biology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.|Departments of Dan L. Duncan Cancer Center, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Departments of Pathology and Immunology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.|Departments of Molecular and Cellular Biology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.|Departments of Molecular Physiology and Biophysics, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
mesh_terms: D017398:Alternative Splicing / Q000235:genetics* / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D064326:MEF2 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D024510:Muscle Development / Q000235:genetics* / Q000502:physiology; D032446:Myoblasts / Q000502:physiology*; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000502:physiology*; D017423:Sequence Analysis, RNA; D054460:rho-Associated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D064326:MEF2 Transcription Factors; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D012313:RNA; D054460:rho-Associated Kinases
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