title: The splicing regulator Rbfox2 is required for both cerebellar development and mature motor function.
abstract: The Rbfox proteins (Rbfox1, Rbfox2, and Rbfox3) regulate the alternative splicing of many important neuronal transcripts and have been implicated in a variety of neurological disorders. However, their roles in brain development and function are not well understood, in part due to redundancy in their activities. Here we show that, unlike Rbfox1 deletion, the CNS-specific deletion of Rbfox2 disrupts cerebellar development. Genome-wide analysis of Rbfox2(-/-) brain RNA identifies numerous splicing changes altering proteins important both for brain development and mature neuronal function. To separate developmental defects from alterations in the physiology of mature cells, Rbfox1 and Rbfox2 were deleted from mature Purkinje cells, resulting in highly irregular firing. Notably, the Scn8a mRNA encoding the Na(v)1.6 sodium channel, a key mediator of Purkinje cell pacemaking, is improperly spliced in RbFox2 and Rbfox1 mutant brains, leading to highly reduced protein expression. Thus, Rbfox2 protein controls a post-transcriptional program required for proper brain development. Rbfox2 is subsequently required with Rbfox1 to maintain mature neuronal physiology, specifically Purkinje cell pacemaking, through their shared control of sodium channel transcript splicing.
authors.affiliation: Molecular Biology Institute, University of California at Los Angeles, CA 90095, USA.
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Gehman
authors.forename: Pratap
authors.initials: P
authors.lastname: Meera
authors.forename: Peter
authors.initials: P
authors.lastname: Stoilov
authors.forename: Lily
authors.initials: L
authors.lastname: Shiue
authors.forename: Janelle E
authors.initials: JE
authors.lastname: O'Brien
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.forename: Manuel
authors.initials: M
authors.lastname: Ares
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Otis
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Black
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C558929:Rbfox2 protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels