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Elife. 2018 Oct 4;7. pii: e33337. doi: 10.7554/eLife.33337.

Cellular localization of the cell cycle inhibitor Cdkn1c controls growth arrest of adult skeletal muscle stem cells.

Author information

1
Inserm, IMRB U955-E10, F-94010, Créteil, France.
2
Ecole Nationale Veterinaire d'Alfort, Faculté de medecine, F-94000, Université Paris-Est Creteil, Maison Alfort, France.
3
Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, United States.
4
Etablissement Français du Sang, Créteil, France.
5
APHP, Hopitaux Universitaires Henri Mondor, DHU Pepsy & Centre de Référence des Maladies Neuromusculaires GNMH, Créteil, France.

Abstract

Adult skeletal muscle maintenance and regeneration depend on efficient muscle stem cell (MuSC) functions. The mechanisms coordinating cell cycle with activation, renewal, and differentiation of MuSCs remain poorly understood. Here, we investigated how adult MuSCs are regulated by CDKN1c (p57kip2), a cyclin-dependent kinase inhibitor, using mouse molecular genetics. In the absence of CDKN1c, skeletal muscle repair is severely impaired after injury. We show that CDKN1c is not expressed in quiescent MuSCs, while being induced in activated and proliferating myoblasts and maintained in differentiating myogenic cells. In agreement, isolated Cdkn1c-deficient primary myoblasts display differentiation defects and increased proliferation. We further show that the subcellular localization of CDKN1c is dynamic; while CDKN1c is initially localized to the cytoplasm of activated/proliferating myoblasts, progressive nuclear translocation leads to growth arrest during differentiation. We propose that CDKN1c activity is restricted to differentiating myoblasts by regulated cyto-nuclear relocalization, coordinating the balance between proliferation and growth arrest.

KEYWORDS:

cell cycle; cyclin-dependent kinase inhibitors; developmental biology; mouse; muscle regeneration; p57; regenerative medicine; satellite cells; stem cells

PMID:
30284969
PMCID:
PMC6172026
DOI:
10.7554/eLife.33337
[Indexed for MEDLINE]
Free PMC Article

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