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

Author

Listed:
  • Caroline E. Brun

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Marie-Claude Sincennes

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Alexander Y. T. Lin

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Derek Hall

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • 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
    University of Ottawa)

  • 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
    University of Ottawa
    University of Ottawa)

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.

Suggested Citation

  • Caroline E. Brun & Marie-Claude Sincennes & Alexander Y. T. Lin & Derek Hall & William Jarassier & Peter Feige & Fabien Le Grand & Michael A. Rudnicki, 2022. "GLI3 regulates muscle stem cell entry into GAlert and self-renewal," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31695-5
    DOI: 10.1038/s41467-022-31695-5
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    References listed on IDEAS

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    1. Joseph T. Rodgers & Katherine Y. King & Jamie O. Brett & Melinda J. Cromie & Gregory W. Charville & Katie K. Maguire & Christopher Brunson & Namrata Mastey & Ling Liu & Chang-Ru Tsai & Margaret A. Goo, 2014. "mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert," Nature, Nature, vol. 510(7505), pages 393-396, June.
    2. Akinobu Matsumoto & Alessandra Pasut & Masaki Matsumoto & Riu Yamashita & Jacqueline Fung & Emanuele Monteleone & Alan Saghatelian & Keiichi I. Nakayama & John G. Clohessy & Pier Paolo Pandolfi, 2017. "mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide," Nature, Nature, vol. 541(7636), pages 228-232, January.
    3. Meryem B. Baghdadi & David Castel & Léo Machado & So-ichiro Fukada & David E. Birk & Frederic Relaix & Shahragim Tajbakhsh & Philippos Mourikis, 2018. "Reciprocal signalling by Notch–Collagen V–CALCR retains muscle stem cells in their niche," Nature, Nature, vol. 557(7707), pages 714-718, May.
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    Cited by:

    1. Alessandra M. Norris & Ambili Bai Appu & Connor D. Johnson & Lylybell Y. Zhou & David W. McKellar & Marie-Ange Renault & David Hammers & Benjamin D. Cosgrove & Daniel Kopinke, 2023. "Hedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jiayin Peng & Lili Han & Biao Liu & Jiawen Song & Yuang Wang & Kunpeng Wang & Qian Guo & XinYan Liu & Yu Li & Jujin Zhang & Wenqing Wu & Sheng Li & Xin Fu & Cheng-le Zhuang & Weikang Zhang & Shengbao , 2023. "Gli1 marks a sentinel muscle stem cell population for muscle regeneration," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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