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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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HITS-CLIP yields genome-wide insights into brain alternative RNA processing
Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., et al. (2008) · Nature · doi:10.1038/nature07488 · Cited by 1,352
“These tags spanned 11.5kb, but were very heavily concentrated around splice sites, in positions that corresponded extremely well with the bioinformatically predicted Nova map18, and with prior biochemical analysis of Nova-dependent splicing21 22 23 (Fig.”
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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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