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Antagonistic regulation of p57kip2 by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest

2014; The Company of Biologists; Volume: 141; Issue: 14 Linguagem: Inglês

10.1242/dev.110155

1477-9129

Antoine Zalc, Shinichiro Hayashi, Frédéric Auradé, Dominique Bröhl, Ted Hung‐Tse Chang, Despoina Mademtzoglou, Philippos Mourikis, Zizhen Yao, Yi Cao, Carmen Birchmeier, Frédéric Relaix,

Developmental Biology and Gene Regulation

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 (p21cip1 and p57kip2), 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 p21cip1 and p57kip2 expression in muscle progenitor cells. Finally, we identify a muscle-specific regulatory element of p57kip2 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 p57kip2 enhancer to regulate the decision between progenitor cell maintenance and muscle differentiation.