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

作者:Wang, Chao; Wang, Min; Arrington, Justine; Shan, Tizhong; Yue, Feng; Nie, Yaohui; Tao, Weiguo Andy; Kuang, Shihuan*
来源:Development, 2017, 144(2): 235-247.
DOI:10.1242/dev.138099

摘要

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.

  • 出版日期2017-1-15