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Development. 2017 Jan 15;144(2):235-247. doi: 10.1242/dev.138099. Epub 2016 Dec 19.

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors.

Author information

1
Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA.
2
Department of Chemistry, Purdue University, West Lafayette, IN 47906, USA.
3
Department of Biochemistry, Purdue University, West Lafayette, IN 47906, USA.
4
Center for Cancer Research, Purdue University, West Lafayette, IN 47906, USA.
5
Department of Animal Science, Purdue University, West Lafayette, IN 47906, USA skuang@purdue.edu.

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.

KEYWORDS:

Ascl2; MRF; Myogenic progenitor cell; Repressor; Self-renewal

PMID:
27993983
PMCID:
PMC5394758
DOI:
10.1242/dev.138099
[Indexed for MEDLINE]
Free PMC Article

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