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

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 <u><u>CDKN1c</u></u> (p57^kip2), a cyclin-dependent kinase inhibitor, using mouse molecular genetics. In the absence of <u><u>CDKN1c</u></u>, skeletal muscle repair is severely impaired after injury. We show that <u><u>CDKN1c</u></u> is not expressed in quiescent MuSCs, while being induced in activated and proliferating myoblasts and maintained in differentiating myogenic cells. In agreement, isolated <i>Cdkn1c</i>-deficient primary myoblasts display differentiation defects and increased proliferation. We further show that the subcellular localization of <u><u>CDKN1c</u></u> is dynamic; while <u><u>CDKN1c</u></u> is initially localized to the cytoplasm of activated/proliferating myoblasts, progressive nuclear translocation leads to growth arrest during differentiation. We propose that <u><u>CDKN1c</u></u> activity is restricted to differentiating myoblasts by regulated cyto-nuclear relocalization, coordinating the balance between proliferation and growth arrest.