title: Rbfox proteins regulate tissue-specific alternative splicing of Mef2D required for muscle differentiation.
abstract: Among the Mef2 family of transcription factors, Mef2D is unique in that it undergoes tissue-specific splicing to generate an isoform that is essential for muscle differentiation. However, the mechanisms mediating this muscle-specific processing of Mef2D remain unknown. Using bioinformatics, we identified Rbfox proteins as putative modulators of Mef2D muscle-specific splicing. Accordingly, we found direct and specific Rbfox1 and Rbfox2 binding to Mef2D pre-mRNA in vivo. Gain- and loss-of-function experiments demonstrated that Rbfox1 and Rbfox2 cooperate in promoting Mef2D splicing and subsequent myogenesis. Thus, our findings reveal a new role for Rbfox proteins in regulating myogenesis through activation of essential muscle-specific splicing events.
authors.affiliation: Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, 20132 Milan, Italy Università Vita-Salute San Raffaele, 20132 Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Runfola
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
authors.forename: Soji
authors.initials: S
authors.lastname: Sebastian
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
authors.forename: F Jeffrey
authors.initials: FJ
authors.lastname: Dilworth
authors.affiliation: Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, 20132 Milan, Italy gabellini.davide@hsr.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Gabellini
mesh_terms: D017398:Alternative Splicing / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D064326:MEF2 Transcription Factors / Q000235:genetics; D051379:Mice; D024510:Muscle Development / Q000235:genetics / Q000502:physiology; D009132:Muscles / Q000166:cytology; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C465036:Rbfox1 protein, mouse; C558929:Rbfox2 protein, mouse
keywords: Alternative splicing; Mef2; Muscle differentiation; Rbfox