Alternative polyadenylation of Pax3 controls muscle stem cell fate and muscle function
Open accessAbstract
Adult stem cells are essential for tissue homeostasis. In skeletal muscle, muscle stem cells (MuSCs) reside in a quiescent state, but little is known about the mechanisms that control homeostatic turnover. Here we show that, in mice, the variation in MuSC activation rate among different muscles (for example, limb versus diaphragm muscles) is determined by the levels of the transcription factor Pax3. We further show that Pax3 levels are controlled by alternative polyadenylation of its transcript, which is regulated by the small nucleolar RNA U1. Isoforms of the Pax3 messenger RNA that differ in their 3' untranslated regions are differentially susceptible to regulation by microRNA miR206, which results in varying levels of the Pax3 protein in vivo. These findings highlight a previously unrecognized mechanism of the homeostatic regulation of stem cell fate by multiple RNA species.
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Highly regenerative Pax3+ MuSCs activate more rapidly than Pax3− counterparts (P<0.001).
“Similar to our experiment in LRCs/nonLRCs, we found that highly regenerative Pax3+ MuSCs also activate more rapidly than Pax3− counterparts (Fig. 5H; P<0.001, Wald test, logistic regression), consistent with a report by De Morree et al. (2019).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as De Morree et al., 2019
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- Authors
- de Morree, A., Klein, J. D. D., Gan, Q., Farup, J., Urtasun, A., Kanugovi, A., Bilen, B., van Velthoven, C. T. J., Quarta, M., & Rando, T. A.
- Affiliations
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Medicine (US)
- Aarhus University (DK)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Rando, Thomas A.
- ORCID
- Venue
- Science
- Published
- 2019-11-08
- Volume
- 366
- Issue
- 6466
- Pages
- 734-738
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7046176
- OpenAlex
- W2985425244
- Cited by
- 81
- References
- 26
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 15 · 2023: 12 · 2022: 7 · 2021: 16 · 2020: 9 · 2019: 2
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01 AR062185, R37 AG023806, P01 AG036695)
- U.S. Department of Veterans Affairs (BLR&D Merit Review)
- Glenn Foundation for Medical Research
- Muscular Dystrophy Association (MDA313960)
- FSH Society
- Lundbeckfonden (R232-2016-2459)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Pax3, alternative polyadenylation, muscle stem cells, skeletal muscle homeostasis, miR-206, 3' untranslated region, stem cell quiescence, stem cell activation, muscle regeneration, protein isoforms
- MeSH terms
- PAX3 Transcription Factor, Animals, Mice, Mutant Strains, RNA, Messenger, Ribonucleoprotein, U1 Small Nuclear, Muscle, Skeletal, 3' Untranslated Regions, Polyadenylation, Myoblasts, Skeletal, MicroRNAs, Mice, Gene Knockdown Techniques
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