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

Development. 2014 Jul;141(14):2780-90. doi: 10.1242/dev.110155.


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: Cdkn1; Cell cycle regulation; MRF; Myogenesis; Notch signaling; p57kip2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism*
  • Enhancer Elements, Genetic / genetics
  • Extremities / embryology
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / metabolism*
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Mice
  • Mice, Transgenic
  • Muscle Development
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / embryology
  • Muscle, Skeletal / growth & development*
  • Muscle, Skeletal / metabolism
  • MyoD Protein / genetics
  • MyoD Protein / metabolism*
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Myogenic Regulatory Factor 5 / metabolism*
  • Organ Specificity
  • PAX7 Transcription Factor / metabolism
  • Receptors, Notch / metabolism*
  • Signal Transduction
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Transcription Factor HES-1


  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p57
  • Hes1 protein, mouse
  • Hey1 protein, mouse
  • Homeodomain Proteins
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Myf5 protein, mouse
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Myogenic Regulatory Factor 5
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Rbpj protein, mouse
  • Receptors, Notch
  • Transcription Factor HES-1