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Cited by 17RNA Research and SplicingIon channel regulation and functionRNA regulation and disease

Cell-Specific RNA Binding Protein Rbfox2 Regulates CaV2.2 mRNA Exon Composition and CaV2.2 Current Size

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Allen, Summer E., Toro, Cecilia P., Andrade, Arturo, López-Soto, Eduardo J., Denome, Sylvia, Lipscombe, Diane·2017·eneuro
DOI 10.1523/eneuro.0332-16.2017PMC PMC5633781
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Abstract

The majority of multiexon mammalian genes contain alternatively spliced exons that have unique expression patterns in different cell populations and that have important cell functions. The expression profiles of alternative exons are controlled by cell-specific splicing factors that can promote exon inclusion or exon skipping but with few exceptions we do not know which specific splicing factors control the expression of alternatively spliced exons of known biological function. Many ion channel genes undergo extensive alternative splicing including Cacna1b that encodes the voltage-gated Ca V 2.2 α1 subunit. Alternatively spliced exon 18a in Cacna1b RNA encodes 21 amino acids in the II-III loop of Ca V 2.2, and its expression differs across the nervous system and over development. Genome-wide, protein-RNA binding analyses coupled to high-throughput RNA sequencing show that RNA binding Fox (Rbfox) proteins associate with Ca V 2.2 (Cacna1b) pre-mRNAs. Here, we link Rbfox2 to suppression of e18a. We show increased e18a inclusion in Ca V 2.2 mRNAs: (1) after siRNA knockdown of Rbfox2 in a neuronal cell line and (2) in RNA from sympathetic neurons of adult compared to early postnatal mice. By immunoprecipitation of Rbfox2-RNA complexes followed by qPCR, we demonstrate reduced Rbfox2 binding upstream of e18a in RNA from sympathetic neurons of adult compared to early postnatal mice. Ca V 2.2 currents in cell lines and in sympathetic neurons expressing only e18a-Ca V 2.2 are larger compared to currents from those expressing only Δ18a-Ca V 2.2. We conclude that Rbfox2 represses e18a inclusion during pre-mRNA splicing of Ca V 2.2, limiting the size of Ca V 2.2 currents early in development in certain neuronal populations.

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  • Rbfox proteins associate with CaV2.2, regulating splicing of specific exons in peripheral neurons.

    “RNA-binding Fox (Rbfox) proteins associate with CaV2.2, regulating the splicing of specific exons in peripheral neurons99”

    From CYFIP1 governs the development of cortical axons by modulating calcium availability (2025) · cites this paper as [99]

    The Introduction reports that Rbfox2 binds CaV2.2 pre-mRNA near exon e18a and suppresses its inclusion in early postnatal sympathetic neurons. The Discussion says the study directly demonstrates this for Rbfox2, while roles for Rbfox1 and Rbfox3 are not excluded—not established. The claim’s plural references to Rbfox proteins and specific exons therefore go beyond the evidence shown. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Allen, S. E., Toro, C. P., Andrade, A., López-Soto, E. J., Denome, S., & Lipscombe, D.
Affiliations
  • Brown University (US)
  • Linfield College (US)
  • University of New Hampshire (US)
Corresponding author
Lipscombe, Diane
ORCID
Venue
eneuro
Publisher
Society for Neuroscience
Published
2017-09
Volume
4
Issue
5
Pages
ENEURO.0332-16.2017
ISSN
2373-2822 (ISSN-L)
DOI
10.1523/eneuro.0332-16.2017
PMC
PMC5633781
OpenAlex
W2759819776
Cited by
17
References
9
Citations by year
2026: 1 · 2025: 2 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 6 · 2018: 1
FWCI
1.12
Type
journal article
Language
en
Open access
Licence
Locations
  • eNeuro (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Sidney Frank Predoctoral Fewlloship
  • Charles A Dana Interdisciplinary Fellowship
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (F31NS066691, F31NS066712, NS55251)
  • HHS | NIH | National Institute of Mental Health (R00 MH099405)
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
RBFOX2, CaV2.2, CACNA1B, alternative splicing, exon skipping, RNA-binding proteins, voltage-gated calcium channels, sympathetic neurons, postnatal development, ion channel currents, pre-mRNA splicing regulation
MeSH terms
RNA Splicing Factors, Action Potentials, Animals, Animals, Newborn, Cells, Cultured, Exons, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Models, Molecular, Neurons, RNA, Messenger, Superior Cervical Ganglion, Gene Expression Regulation, Developmental, Calcium Channels, N-Type, RNA, Small Interfering, Mice, Rats

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