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Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors
- Publication Year :
- 2017
- Publisher :
- The Company of Biologists Ltd, 2017.
-
Abstract
- Myogenic regulatory factors (MRFs) including Myf5, MyoD and Myog are muscle-specific transcriptional factors orchestrating myogenesis. Although MRFs are essential for myogenic commitment and differentiation, timely repression of their activity is necessary for self-renewal and maintenance of muscle stem cells (satellite cells). Here we define a novel inhibitor of MRFs: the achaete-scute homologue 2 (Ascl2). During development, Ascl2 is transiently detected in a subpopulation of Pax7+MyoD+ progenitors (myoblasts) that become Pax7+MyoD− satellite cells prior to birth, but not detectable in postnatal satellite cells. Knockout of Ascl2 in embryonic myoblasts decreases both the number of Pax7+ cells and the proportion of Pax7+MyoD− cells. Conversely, overexpression of Ascl2 inhibits the proliferation and differentiation of cultured myoblasts, and impairs regeneration of injured muscles. At the molecular level, Ascl2 competes with MRFs for binding to E-boxes in the promoters of muscle genes, without activating gene transcription. Ascl2 also forms heterodimer with classical E-proteins to sequester their transcriptional activity on MRFs. Accordingly, MyoD or Myog expression rescues myogenic differentiation despite Ascl2 overexpression. Finally, Ascl2 expression is regulated by Notch signaling, a key governor of satellite cell self-renewal. These data together demonstrate that Ascl2 inhibits myogenic differentiation by targeting MRFs, and facilitates generation of postnatal satellite cells.
- Subjects :
- 0301 basic medicine
Transcriptional Activation
Satellite Cells, Skeletal Muscle
Biology
MyoD
Muscle Development
03 medical and health sciences
Mice
Basic Helix-Loop-Helix Transcription Factors
Myocyte
Animals
Molecular Biology
Myogenin
Cells, Cultured
Mice, Knockout
Myogenesis
Gene Expression Regulation, Developmental
Cell Differentiation
musculoskeletal system
Stem Cells and Regeneration
Embryo, Mammalian
Embryonic stem cell
030104 developmental biology
Myogenic Regulatory Factors
Myogenic regulatory factors
Cancer research
MYF5
Female
Stem cell
tissues
Developmental Biology
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....cba846ebf15a3eb906a5a0af4bc7da6e