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Neuron-specific ELAV/Hu proteins suppress HuR mRNA during neuronal differentiation by alternative polyadenylation
Open accessAbstract
The ubiquitously expressed RNA-binding protein HuR increases the stability and translation of mRNAs encoding growth regulatory proteins that promote proliferation in a variety of cell types. However, the three neuron-specific ELAV/Hu proteins, HuB, HuC and HuD, while binding to the same types of mRNAs, are required instead for neuronal differentiation, and it becomes difficult to reconcile these contrary functions when all four Hu proteins are expressed in the same neuron. HuR mRNA exists as three alternatively polyadenylated variants, a 1.5-kb testes-specific mRNA isoform, a ubiquitous 2.4-kb isoform and a 6.0-kb isoform that we now show is induced during neuronal differentiation and appears to be neuron-specific. This 6.0-kb neuron-specific mRNA isoform is inherently less stable and produces less HuR protein than the ubiquitous 2.4-kb mRNA. Furthermore, we show that neuronal HuB, HuC and HuD, as well as HuR itself, can bind at the 2.4-kb mRNA polyadenylation site, and when overexpressed can affect alternative polyadenylation to generate an extended HuR 3'-UTR that is translationally suppressed. We propose that the regulation of HuR protein expression by alternative polyadenylation allows neurons to post-transcriptionally regulate mRNAs-encoding factors required for proliferation versus differentiation to facilitate neuronal differentiation.
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“All four Hu members were found to bind and block U-rich sequences near the 2.4-kb polyadenylation site and thereby promote expression of the 6.0-kb transcript.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Mansfield and Keene 2011
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“Moreover, all four Hu proteins were recently demonstrated to differentially regulate alternative polyadenylation of HuR in neurons (Mansfield and Keene 2011; also see Dai et al. 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Mansfield and Keene 2011
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“Mansfield and Keene showed that there are three different HuR mRNA polyadenylation variants (1.5, 2.4, and 6.0 kb), which differ in 3′ UTR length.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Mansfield and Keene 2011
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“Since the 6.0-kb variant is less stable and not as efficiently translated as the 2.4-kb transcript, the authors postulated that the reduction of HuR expression prevents HuR’s ability to promote proliferation and thereby permits neurons to terminally differentiate (Mansfield and Keene 2011).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Mansfield and Keene 2011
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Metadata
- Authors
- Mansfield, K. D., & Keene, J. D.
- Affiliations
- Duke University (US)
- Corresponding author
- Mansfield, Kyle D.
- ORCID
- Mansfield, Kyle D.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-12-01
- Volume
- 40
- Issue
- 6
- Pages
- 2734-2746
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3315332
- OpenAlex
- W2091095457
- Cited by
- 112
- References
- 66
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 4 · 2017: 10 · 2016: 7 · 2015: 5 · 2014: 13 · 2013: 15 · 2012: 5
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (0842621)
- National Institutes of Health (5f32ns059100-02)
- National Cancer Institute (R01CA157268)
- National Institute of Neurological Disorders and Stroke (5F32NS059100-02)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- HuR, hubs, HuC, HUD, alternative polyadenylation, neuronal differentiation, mRNA stability, 3' untranslated region, post-transcriptional regulation, RNA-binding proteins, mRNA isoforms, translation suppression
- MeSH terms
- Cell Line, Gene Expression Regulation, Humans, Neurons, Protein Biosynthesis, 3' Untranslated Regions, RNA Stability, Polyadenylation, ELAV Proteins, Neurogenesis, RNA Isoforms
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