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Antagonistic regulation of p57(kip2) by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest

Item Type:Article
Title:Antagonistic regulation of p57(kip2) by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest
Creators Name:Zalc, A. and Hayashi, S. and Auradé, F. and Bröhl, D. and Chang, T. and Mademtzoglou, D. and Mourikis, P. and Yao, Z. and Cao, Y. and Birchmeier, C. and Relaix, F.
Abstract:A central question in development is to define how the equilibrium between cell proliferation and differentiation is temporally and spatially regulated during tissue formation. Here, we address how interactions between cyclin-dependent kinase inhibitors essential for myogenic growth arrest (p21(cip1) and p57(kip2)), the Notch pathway and myogenic regulatory factors (MRFs) orchestrate the proliferation, specification and differentiation of muscle progenitor cells. We first show that cell cycle exit and myogenic differentiation can be uncoupled. In addition, we establish that skeletal muscle progenitor cells require Notch signaling to maintain their cycling status. Using several mouse models combined with ex vivo studies, we demonstrate that Notch signaling is required to repress p21(cip1) and p57(kip2) expression in muscle progenitor cells. Finally, we identify a muscle-specific regulatory element of p57(kip2) directly activated by MRFs in myoblasts but repressed by the Notch targets Hes1/Hey1 in progenitor cells. We propose a molecular mechanism whereby information provided by Hes/Hey downstream of Notch as well as MRF activities are integrated at the level of the p57(kip2) enhancer to regulate the decision between progenitor cell maintenance and muscle differentiation.
Keywords:Myogenesis, Cell Cycle Regulation, p57(kip2), Cdkn1, Notch Signaling, MRF, Animals, Mice
Source:Development
ISSN:0950-1991
Publisher:Company of Biologists (U.K.)
Volume:141
Number:14
Page Range:2780-2790
Date:July 2014
Official Publication:https://doi.org/10.1242/dev.110155
PubMed:View item in PubMed

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