title: Rbfox proteins regulate alternative splicing of neuronal sodium channel SCN8A.
abstract: The SCN8A gene encodes the voltage-gated sodium channel Na(v)1.6, a major channel in neurons of the CNS and PNS. SCN8A contains two alternative exons,18N and 18A, that exhibit tissue specific splicing. In brain, the major SCN8A transcript contains exon 18A and encodes the full-length sodium channel. In other tissues, the major transcript contains exon 18N and encodes a truncated protein, due to the presence of an in-frame stop codon. Selection of exon 18A is therefore essential for generation of a functional channel protein, but the proteins involved in this selection have not been identified. Using a 2.6 kb Scn8a minigene containing exons 18N and 18A, we demonstrate that co-transfection with Fox-1 or Fox-2 initiates inclusion of exon 18A. This effect is dependent on the consensus Fox binding site located 28 bp downstream of exon 18A. We examined the alternative splicing of human SCN8A and found that the postnatal switch to exon 18A is completed later than 10 months of age. In purified cell populations, transcripts containing exon 18A predominate in neurons but are not present in oligodendrocytes or astrocytes. Transcripts containing exon 18N appear to be degraded by nonsense-mediated decay in HEK cells. Our data indicate that RBFOX proteins contribute to the cell-specific expression of Na(v)1.6 channels in mature neurons.
authors: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
authors: Janelle E
authors: JE
authors: O'Brien
authors: Valerie L
authors: VL
authors: Drews
authors: Julie M
authors: JM
authors: Jones
authors: Jason C
authors: JC
authors: Dugas
authors: Ben A
authors: BA
authors: Barres
authors: Miriam H
authors: MH
authors: Meisler
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C455479:RBFOX1 protein, human; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C100681:SCN8A protein, human; C507811:Scn8a protein, rat; D015222:Sodium Channels