GLI3 regulates muscle stem cell entry into GAlert and self-renewal

Caroline E. Brun, Marie-Claude Sincennes, Alexander Y. T. Lin, Derek Hall, William Jarassier, Peter Feige, Fabien Le Grand and Michael A. Rudnicki ()
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Caroline E. Brun: Ottawa Hospital Research Institute
Marie-Claude Sincennes: Ottawa Hospital Research Institute
Alexander Y. T. Lin: Ottawa Hospital Research Institute
Derek Hall: Ottawa Hospital Research Institute
William Jarassier: Univ Lyon, Univ Lyon 1, CNRS, INSERM, Pathophysiology and Genetics of Neuron and Muscle, UMR5261, U1315, Institut NeuroMyoGène
Peter Feige: Ottawa Hospital Research Institute
Fabien Le Grand: Univ Lyon, Univ Lyon 1, CNRS, INSERM, Pathophysiology and Genetics of Neuron and Muscle, UMR5261, U1315, Institut NeuroMyoGène
Michael A. Rudnicki: Ottawa Hospital Research Institute

Nature Communications, 2022, vol. 13, issue 1, 1-14

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 G0 dormant state. Strikingly, satellite cells lacking GLI3 enter the GAlert 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.

Date: 2022
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DOI: 10.1038/s41467-022-31695-5

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