GLI3 regulates muscle stem cell entry into GAlert and self-renewal
Caroline Brun, Marie‐Claude Sincennes, Alexander Y. Lin, Derek Hall, William Jarassier, Peter Feige, Fabien Le Grand, Michael A. Rudnicki
Abstract
Abstract Satellite cells are required for the growth, maintenance, and regeneration of skeletal muscle. Quiescent satellite cells possess a primary cilium, a structure that regulates the processing of the GLI family of transcription factors. Here we find that GLI3 processing by the primary cilium plays a critical role for satellite cell function. GLI3 is required to maintain satellite cells in a G 0 dormant state. Strikingly, satellite cells lacking GLI3 enter the G Alert state in the absence of injury. Furthermore, GLI3 depletion stimulates expansion of the stem cell pool. As a result, satellite cells lacking GLI3 display rapid cell-cycle entry, increased proliferation and augmented self-renewal, and markedly enhanced regenerative capacity. At the molecular level, we establish that the loss of GLI3 induces mTORC1 signaling activation. Therefore, our results provide a mechanism by which GLI3 controls mTORC1 signaling, consequently regulating muscle stem cell activation and fate.