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 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.

Androgen receptor in satellite cells is not essential for muscle regenerations

“…The Pax7 CreERT2(Fan)/+ regeneration phenotype is consistent with previous findings (Mademtzoglou et al, 2018) and likely related to expression of only one Pax7 allele after CreERT2 insertion (Lepper et al, 2009). Leaky Cre recombinase activation and downregulation of Hey1, which is required to maintain satellite cells, in Pax7 CreERT2(Fan)/+ mice not treated with tamoxifen (Noguchi et al, 2019) could affect satellite cells during muscle regeneration.…”

Imprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development

“…In the future it will be revealing to dissect the interplay of endogenous p57 KIP2 protein and the here identified genetic element in the regulation of cortical stem cell behavior. Interestingly, it has been shown that the intracellular distribution and localization of p57 KIP2 plays instructive roles in proliferation and differentiation of adult skeletal muscle stem cells 31 . Whether similar mechanisms and/or in combination with the 500 bp element are relevant for RGP proliferation, cortical neuron production and/or cellular survival represent critical open questions that should be clarified in further studies.…”

Stem Cell Quiescence: Dynamism, Restraint, and Cellular Idling

“…Other interesting options include the monitoring of p57 and/or p21 expression in G 0 and/or G 1 . However, their expression patterns are dependent on the stem cell type studied (Cheng et al, 2000;Kippin et al, 2005;Matsumoto et al, 2011;Furutachi et al, 2013;Mademtzoglou et al, 2018). Further development of these and other reporter systems will undoubtedly aid in further identification of quiescent cell populations.…”