title: Antagonistic regulation of p57kip2 by Hes/Hey downstream of Notch signaling and muscle regulatory factors regulates skeletal muscle growth arrest.
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.
authors.affiliation: UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Zalc
authors.affiliation: UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Auradé
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bröhl
authors.affiliation: UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France.
authors.forename: Ted
authors.initials: T
authors.lastname: Chang
authors.affiliation: UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France.
authors.forename: Despoina
authors.initials: D
authors.lastname: Mademtzoglou
authors.affiliation: UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France.
authors.forename: Philippos
authors.initials: P
authors.lastname: Mourikis
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.affiliation: UPMC Paris 06, U 974, Paris, F-75013, France INSERM, Avenir Team, Pitié-Salpétrière, Paris, F-75013, France Institut de Myologie, Paris, F-75013, France frelaix@gmail.com.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Relaix
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005121:Extremities / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism*; D009928:Organ Specificity; D051763:PAX7 Transcription Factor / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D017570:MyoD Protein; D051787:Myogenic Regulatory Factor 5; D051763:PAX7 Transcription Factor; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; C497418:Myf5 protein, mouse; C057363:MyoD1 myogenic differentiation protein; C497322:Pax7 protein, mouse; C497571:Rbpj protein, mouse
keywords: Cdkn1; Cell cycle regulation; MRF; Myogenesis; Notch signaling; p57kip2