Nova-1 Regulates Neuron-Specific Alternative Splicing and Is Essential for Neuronal Viability
Open accessAbstract
We have combined genetic and biochemical approaches to analyze the function of the RNA-binding protein Nova-1, the paraneoplastic opsoclonus-myoclonus ataxia (POMA) antigen. Nova-1 null mice die postnatally from a motor deficit associated with apoptotic death of spinal and brainstem neurons. Nova-1 null mice show specific splicing defects in two inhibitory receptor pre-mRNAs, glycine alpha2 exon 3A (GlyRalpha2 E3A) and GABA(A) exon gamma2L. Nova protein in brain extracts specifically bound to a previously identified GlyRalpha2 intronic (UCAUY)3 Nova target sequence, and Nova-1 acted directly on this element to increase E3A splicing in cotransfection assays. We conclude that Nova-1 binds RNA in a sequence-specific manner to regulate neuronal pre-mRNA alternative splicing; the defect in splicing in Nova-1 null mice provides a model for understanding the motor dysfunction in POMA.
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NOVA1 is an interactor of ELAVL4, a gene that codes for a neuronal-specific RNA-binding protein and might have been under positive selection in humans.
“NOVA1101, which is an interactor of ELAVL4102, a gene that codes for a neuronal-specific RNA-binding protein and might have been under positive selection in humans33,36.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [101]
Nova1/2 dKO mice, but not single-knockout mice, show fewer acetylcholine receptor clusters and a loss of apposition between AChR clusters and phrenic nerve terminals.
“the dKO mice, but not the single-knockout mice, show fewer acetylcholine receptor (AChR) clusters and a loss of apposition between AChR clusters and phrenic nerve terminals”
From The neurogenetics of alternative splicing (2016) · cites this paper as [38]
Nova1−/− mice appear normal at birth but die in the second postnatal week with motor neuron apoptosis, profound motor failure and action-induced tremors.
“Nova1−/− mice appear normal at birth, but die in the second postnatal week with motor neuron apoptosis, profound motor failure and action-induced tremors37,38.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [38]
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- Authors
- Jensen, K. B., Dredge, B. K., Stefani, G., Zhong, R., Buckanovich, R. J., Okano, H. J., Yang, Y. Y. L., & Darnell, R. B.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Darnell, Robert B
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2000-02
- Volume
- 25
- Issue
- 2
- Pages
- 359-371
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2073654740
- Cited by
- 426
- References
- 83
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 10 · 2023: 18 · 2022: 20 · 2021: 7 · 2020: 11 · 2019: 14 · 2018: 11 · 2017: 16 · 2016: 15 · 2015: 14 · 2014: 18 · 2013: 17 · 2012: 13
- FWCI
- 8.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01 NS34389, R01NS034389)
- 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
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- RNA-binding proteins, alternative splicing, neuronal viability, neuronal apoptosis, RNA binding specificity, motor impairment
- MeSH terms
- Neuro-Oncological Ventral Antigen, Animals, Antigens, Neoplasm, Brain Chemistry, Brain Stem, Cell Survival, Exons, Genotype, Mice, Inbred C57BL, Motor Neurons, Nerve Tissue Proteins, Protein Binding, Receptors, GABA-A, Ribonucleoproteins, RNA Precursors, Spinal Cord, RNA-Binding Proteins, Apoptosis, Gene Deletion, Alternative Splicing, Receptors, Glycine, Mice, Knockout, Gene Expression Regulation, Developmental, In Situ Nick-End Labeling, Mice
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