Constitutive Notch Activation Upregulates Pax7 and promotes the self-renewal of skeletal muscle satellite cells

Yefei Wen, Pengpeng Bi, Weiyi Liu, Atsushi Asakura, Charles Keller, Shihuan Kuang

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Notch signaling is a conserved cell fate regulator during development and postnatal tissue regeneration. Using skeletal muscle satellite cells as a model and through myogenic cell lineage-specific NICDOE (overexpression of constitutively activated Notch 1 intracellular domain), here we investigate how Notch signaling regulates the cell fate choice of muscle stem cells. We show that in addition to inhibiting MyoD and myogenic differentiation, NICDOE upregulates Pax7 and promotes the self-renewal of satellite cell-derived primary myoblasts in culture. Using MyoD-/- myoblasts, we further show that NICDOE upregulates Pax7 independently of MyoD inhibition. In striking contrast to previous observations, NICDOE also inhibits S-phase entry and Ki67 expression and thus reduces the proliferation of primary myoblasts. Overexpression of canonical Notch target genes mimics the inhibitory effects of NICDOE on MyoD and Ki67 but not the stimulatory effect on Pax7. Instead, NICD regulates Pax7 through interaction with RBP-Jk, which binds to two consensus sites upstream of the Pax7 gene. Importantly, satellite cell-specific NICDOE results in impaired regeneration of skeletal muscles along with increased Pax7+ mononuclear cells. Our results establish a role of Notch signaling in actively promoting the self-renewal of muscle stem cells through direct regulation of Pax7.

Original languageEnglish (US)
Pages (from-to)2300-2311
Number of pages12
JournalMolecular and Cellular Biology
Volume32
Issue number12
DOIs
StatePublished - Jun 15 2012

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Skeletal Muscle Satellite Cells
Myoblasts
Up-Regulation
Muscle Cells
Regeneration
Cell Lineage
S Phase
Genes
Skeletal Muscle
Stem Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Constitutive Notch Activation Upregulates Pax7 and promotes the self-renewal of skeletal muscle satellite cells. / Wen, Yefei; Bi, Pengpeng; Liu, Weiyi; Asakura, Atsushi; Keller, Charles; Kuang, Shihuan.

In: Molecular and Cellular Biology, Vol. 32, No. 12, 15.06.2012, p. 2300-2311.

Research output: Contribution to journalArticle

Wen, Yefei ; Bi, Pengpeng ; Liu, Weiyi ; Asakura, Atsushi ; Keller, Charles ; Kuang, Shihuan. / Constitutive Notch Activation Upregulates Pax7 and promotes the self-renewal of skeletal muscle satellite cells. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 12. pp. 2300-2311.
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