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Nova autoregulation reveals dual functions in neuronal splicing
Open accessAbstract
The Nova family of neuron-specific RNA-binding proteins were originally identified as targets in an autoimmune neurologic disease characterized by failure of motor inhibition. Nova-1 regulates alternative splicing of pre-mRNAs encoding the inhibitory neurotransmitter receptor subunits GABA(A)Rgamma2 and GlyRalpha2 by directly binding intronic elements, resulting in enhancement of exon inclusion. Here we identify exon E4 in the Nova-1 pre-mRNA itself, encoding a phosphorylated protein domain, as an additional target of Nova-dependent splicing regulation in the mouse spinal cord. Nova binding to E4 is necessary and sufficient for Nova-dependent exon exclusion. E4 harbors five repeats of the known Nova-binding tetranucleotide YCAY and mutation of these elements destroys Nova-dependent regulation. Furthermore, swapping of the sites from Nova-1 and GABA(A)Rgamma2 indicates that the ability of Nova to enhance or repress alternative exon inclusion is dependent on the position of the Nova-binding element within the pre-mRNA. These studies demonstrate that in addition to its previously described role as a splicing activator, Nova autoregulates its own expression by acting as a splicing repressor.
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“The mutually exclusive expression pattern of SLM1 and SLM2 is enforced by their cross-regulation via alternative splicing coupled with NMD, as seen with other paralogous pairs of RNA-binding proteins15,20,21,49,53,85,86.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [49]
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Metadata
- Authors
- Dredge, B. K., Stefani, G., Engelhard, C. C., & Darnell, R. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Darnell, Robert B
- Venue
- The EMBO Journal
- Published
- 2005-03-31
- Volume
- 24
- Issue
- 8
- Pages
- 1608-1620
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1142566
- OpenAlex
- W2150107170
- Cited by
- 125
- References
- 30
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 6 · 2014: 4 · 2013: 8 · 2012: 11
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Iris (University of Trento) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Neurological Disorders and Stroke (R01NS040955, R01 NS34389, R01NS034389, NS40955)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- alternative splicing, autoregulation, RNA-binding proteins, exon inclusion, spinal cord neurons, splicing repressor, phosphorylation domain
- MeSH terms
- Neuro-Oncological Ventral Antigen, Amino Acid Sequence, Animals, Antigens, Neoplasm, Base Sequence, Binding Sites, Cell Line, Exons, Gene Expression Regulation, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Receptors, GABA-A, RNA Precursors, Sequence Alignment, RNA-Binding Proteins, Alternative Splicing, Protein Structure, Tertiary, Receptors, Glycine, Mice
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