title: Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration.
abstract: Satellite cells (SCs) are stem cells that mediate skeletal muscle growth and regeneration. Here, we observe that adult quiescent SCs and their activated descendants expressed the homeodomain transcription factor Six1. Genetic disruption of Six1 specifically in adult SCs impaired myogenic cell differentiation, impaired myofiber repair during regeneration, and perturbed homeostasis of the stem cell niche, as indicated by an increase in SC self-renewal. Six1 regulated the expression of the myogenic regulatory factors MyoD and Myogenin, but not Myf5, which suggests that Six1 acts on divergent genetic networks in the embryo and in the adult. Moreover, we demonstrate that Six1 regulates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway during regeneration via direct control of Dusp6 transcription. Muscles lacking Dusp6 were able to regenerate properly but showed a marked increase in SC number after regeneration. We conclude that Six1 homeoproteins act as a rheostat system to ensure proper regeneration of the tissue and replenishment of the stem cell pool during the events that follow skeletal muscle trauma.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris 75014, France. fabien.le-grand@inserm.fr
authors.forename: Fabien
authors.initials: F
authors.lastname: Le Grand
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Grifone
authors.forename: Philippos
authors.initials: P
authors.lastname: Mourikis
authors.forename: Christophe
authors.initials: C
authors.lastname: Houbron
authors.forename: Carine
authors.initials: C
authors.lastname: Gigaud
authors.forename: Julien
authors.initials: J
authors.lastname: Pujol
authors.forename: Marjorie
authors.initials: M
authors.lastname: Maillet
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
authors.forename: Michael
authors.initials: M
authors.lastname: Rudnicki
authors.forename: Shahragim
authors.initials: S
authors.lastname: Tajbakhsh
authors.forename: Pascal
authors.initials: P
authors.lastname: Maire
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism / Q000502:physiology; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051787:Myogenic Regulatory Factor 5; D018006:Myogenic Regulatory Factors; D018008:Myogenin; C490947:Six1 protein, mouse; D014157:Transcription Factors; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse