RT Journal Article
SR Electronic
T1 Satellite cell expansion is mediated by P-eIF2α-dependent <em>Tacc3</em> translation
JF Development
JO Development
FD The Company of Biologists Limited
SP dev194480
DO 10.1242/dev.194480
VO 148
IS 2
A1 Fujita, Ryo
A1 Jamet, Solène
A1 Lean, Graham
A1 Cheng, Harry Chun Man
A1 Hébert, Steven
A1 Kleinman, Claudia L.
A1 Crist, Colin
YR 2021
UL http://dev.biologists.org/content/148/2/dev194480.abstract
AB 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.