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

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

Authors
  • Antoine Zalc
  • Shinichiro Hayashi
  • Frédéric Auradé
  • Dominique Bröhl
  • Ted Chang
  • Despoina Mademtzoglou
  • Philippos Mourikis
  • Zizhen Yao
  • Yi Cao
  • Carmen Birchmeier
  • Frédéric Relaix
Type
Published Article
Journal
Development
Publisher
The Company of Biologists
Volume
141
Issue
14
Pages
2780–2790
Identifiers
DOI: 10.1242/dev.110155
Source
CdV-UPMC
Keywords
License
Green

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.

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