Cited by 49RNA Research and SplicingIon channel regulation and functionRNA regulation and disease

Rbfox proteins regulate alternative splicing of neuronal sodium channel SCN8A

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O'Brien, Janelle E., Drews, Valerie L., Jones, Julie M., Dugas, Jason C., Barres, Ben A., Meisler, Miriam H.·2012·Molecular and Cellular Neuroscience

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.

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Crossref · 10.1016/j.mcn.2011.10.005

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  • Skipping both Scn8a exons 18A and 18N produces an isoform lacking large portions of the third and fourth transmembrane domains.

    “whereas skipping both 18A and 18N produces an isoform that lacks large portions of the third and fourth transmembrane domains146,147”

    From The neurogenetics of alternative splicing (2016) · cites this paper as [147]

  • Inclusion of Scn8a exon 18N introduces a premature termination codon and leads to nonsense-mediated decay.

    “Inclusion of 18N introduces a premature termination codon and leads to nonsense-mediated decay”

    From The neurogenetics of alternative splicing (2016) · cites this paper as [147]

  • Scn8a exons 18A and 18N determine whether a functional 18A+ Scn8a mRNA is produced.

    “Another pair of mutually exclusive exons, 18A and 18N, determine whether a functional 18A+ Scn8a mRNA is produced.”

    From The neurogenetics of alternative splicing (2016) · cites this paper as [147]

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Authors
O'Brien, J. E., Drews, V. L., Jones, J. M., Dugas, J. C., Barres, B. A., & Meisler, M. H.
Affiliations
  • University of Michigan (US)
  • Stanford Medicine (US)
Corresponding author
Meisler, Miriam H.
Venue
Molecular and Cellular Neuroscience
Publisher
Elsevier BV
Published
2012-02
Volume
49
Issue
2
Pages
120-126
ISSN
1044-7431 (ISSN-L)
OpenAlex
W2009882814
Cited by
49
References
62
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 8 · 2022: 1 · 2021: 8 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 3
FWCI
1.30
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH
  • National Multiple Sclerosis Society
  • NIH Predoctoral Training Program in Genetics
  • Rackham School of Graduate Studies at the University of Michigan
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
SCN8A, alternative splicing, nonsense-mediated mRNA decay, postnatal development, minigene, tissue-specific gene expression
MeSH terms
RNA Splicing Factors, Animals, Binding Sites, Brain, Cell Line, Cells, Cultured, Exons, Humans, Nerve Tissue Proteins, Neurons, Repressor Proteins, Sodium Channels, RNA-Binding Proteins, Alternative Splicing, Gene Expression Regulation, Developmental, Rats, HEK293 Cells, NAV1.6 Voltage-Gated Sodium Channel

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