title: Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors.
abstract: Myogenic regulatory factors (MRFs), including Myf5, MyoD (Myod1) and Myog, are muscle-specific transcription factors that orchestrate myogenesis. Although MRFs are essential for myogenic commitment and differentiation, timely repression of their activity is necessary for the self-renewal and maintenance of muscle stem cells (satellite cells). Here, we define Ascl2 as a novel inhibitor of MRFs. During mouse development, Ascl2 is transiently detected in a subpopulation of Pax7+MyoD+progenitors (myoblasts) that become Pax7+MyoD-satellite cells prior to birth, but is not detectable in postnatal satellite cells. Ascl2 knockout 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 the regeneration of injured muscles. Ascl2 competes with MRFs for binding to E-boxes in the promoters of muscle genes, without activating gene transcription. Ascl2 also forms heterodimers with classical E-proteins to sequester their transcriptional activity on MRF genes. Accordingly, MyoD or Myog expression rescues myogenic differentiation despite Ascl2 overexpression. Ascl2 expression is regulated by Notch signaling, a key governor of satellite cell self-renewal. These data demonstrate that Ascl2 inhibits myogenic differentiation by targeting MRFs and facilitates the generation of postnatal satellite cells.
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Arrington
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Tizhong
authors.initials: T
authors.lastname: Shan
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Nie
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, IN 47906, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Weiguo Andy
authors.initials: WA
authors.lastname: Tao
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA skuang@purdue.edu.|Center for Cancer Research, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Shihuan
authors.identifier: 0000-0001-9180-3180
authors.initials: S
authors.lastname: Kuang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics*; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018006:Myogenic Regulatory Factors; C489311:Ascl2 protein, mouse
keywords: Ascl2; MRF; Myogenic progenitor cell; Repressor; Self-renewal