Vertebrate muscle regeneration is driven by satellite cells, resident stem cells that stay quiescent until injury when they proliferate to seed new muscle growth. Quiescent and self-renewing satellite cells reduce protein synthesis by phosphorylating the translation initiation factor eIF2α. While pharmacological inhibition of eIF2α dephosphorylation with sal003 promotes expansion of a self-renewing satellite cell population, some mRNAs are known to escape repression, via P-eIF2α-dependent read-through of inhibitory upstream open reading frames (uORFs). Now, Colin Crist and colleagues investigate the mechanisms by which P-eIF2α promotes satellite cell expansion. Sal003 treatment globally affects the satellite cell transcriptome, with most genes being downregulated. Using mass spectrometry, the authors then identify 140 genes upregulated at the level of protein but not transcript, and find a striking enrichment of genes involved in spindle assembly. One of these genes, Tacc3, encodes a centrosomal protein required for spindle stability – ensuring the fidelity of cell division. Increased Tacc3 translation occurs via P-eIF2α-dependent uORFs in the 5’UTR. TACC3 expression is upregulated in activated satellite cells and downregulated during myogenic differentiation, and Tacc3 knockout hinders expansion of satellite cell colonies ex vivo, promoting their precocious differentiation. Finally, TACC3 is required for satellite cell expansion and for proper and timely regeneration in vivo. Thus, P-eIF2α promotes satellite cell expansion through the selective translation of mRNAs that are required to ensure the fidelity of cell division.
