Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration

• DOI: 10.1083/jcb.201201050
• Publication Date: 2012-09-03T15:33:44Z
• Authors: Fabien Le Grand; Raphaëlle Grifone; Philippos Mourikis; Christophe Houbron; Carine Gigaud; Julien Pujol; Marjorie Maillet; Gilles Pagès; Michael Rudnicki; Shahragim Tajbakhsh; Pascal Maire
• Keywords: Homeodomain Proteins; 0301 basic medicine; Wound Healing; Satellite Cells, Skeletal Muscle; MAP Kinase Signaling System; Stem Cells; Cell Differentiation; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Myofibrils; Myogenic Regulatory Factors; Dual Specificity Phosphatase 6; Animals; Homeostasis; Regeneration; Myogenin; Myogenic Regulatory Factor 5; Muscle, Skeletal; Research Articles; MyoD Protein; Transcription Factors

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.