Handling Editor: Benoit Bruneau
ABSTRACT
Translational control of gene expression is an important regulator of adult stem cell quiescence, activation and self-renewal. In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2α (P-eIF2α). Pharmacological inhibition of the eIF2α phosphatase with the small molecule sal003 maintains P-eIF2α and permits the expansion of satellite cells ex vivo. Paradoxically, P-eIF2α also increases the translation of specific mRNAs, which is mediated by P-eIF2α-dependent read-through of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2α-dependent mRNA translation enables expansion of satellite cells. Using transcriptomic and proteomic analyses, we show a number of genes associated with the assembly of the spindle pole to be upregulated at the level of protein, without corresponding change in mRNA levels, in satellite cells expanded in the presence of sal003. We show that uORFs in the 5′ UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2α-dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: C.C.; Methodology: R.F., S.J., G.L., C.L.K., C.C.; Software: S.H., C.L.K.; Validation: C.C.; Formal analysis: R.F., S.J., G.L., S.H., C.L.K.; Investigation: R.F., S.J., G.L., H.C.M.C., S.H., C.L.K.; Data curation: S.H., C.L.K.; Writing - original draft: C.C.; Writing - review & editing: R.F., S.J., G.L., H.C.M.C., C.C.; Visualization: R.F., S.J., G.L., H.C.M.C., C.C.; Supervision: C.L.K., C.C.; Project administration: C.C.; Funding acquisition: C.C.
Funding
C.C. and coworkers are funded by the Canadian Institutes of Health Research (CIHR; 399258), the Stem Cell Network, the Fonds de Recherche du Québec – Santé (FRQS) and the Richard and Edith Strauss Foundation. R.F. is funded by a Japan Society for the Promotion of Science Overseas Research Fellowship, the Uehara Memorial Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and a Ministry of Education, Culture, Sports, Science and Technology Leading Initiative for Excellent Young Researchers grant. C.L.K. is supported by the CIHR (156086) and the FRQS.
Data availability
RNA-sequencing data have been deposited in GEO under accession number GSE164774.
Supplementary information
Supplementary information available online at https://dev.biologists.org/lookup/doi/10.1242/dev.194480.supplemental
- Received June 25, 2020.
- Accepted December 4, 2020.
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