The transcription factor Lef1 switches partners from β-catenin to Smad3 during muscle stem cell quiescence

Sci Signal. 2018 Jul 24;11(540):eaan3000. doi: 10.1126/scisignal.aan3000.

Abstract

Skeletal muscle stem cells (MuSCs), also known as satellite cells, persist in adult mammals by entering a state of quiescence (G0) during the early postnatal period. Quiescence is reversed during damage-induced regeneration and re-established after regeneration. Entry of cultured myoblasts into G0 is associated with a specific, reversible induction of Wnt target genes, thus implicating members of the Tcf and Lef1 (Tcf/Lef) transcription factor family, which mediate transcriptional responses to Wnt signaling, in the initiation of quiescence. We found that the canonical Wnt effector β-catenin, which cooperates with Tcf/Lef, was dispensable for myoblasts to enter quiescence. Using pharmacological and genetic approaches in cultured C2C12 myoblasts and in MuSCs, we demonstrated that Tcf/Lef activity during quiescence depended not on β-catenin but on the transforming growth factor-β (TGF-β) effector and transcriptional coactivator Smad3, which colocalized with Lef1 at canonical Wnt-responsive elements and directly interacted with Lef1 specifically in G0 Depletion of Smad3, but not β-catenin, reduced Lef1 occupancy at target promoters, Tcf/Lef target gene expression, and self-renewal of myoblasts. In vivo, MuSCs underwent a switch from β-catenin-Lef1 to Smad3-Lef1 interactions during the postnatal switch from proliferation to quiescence, with β-catenin-Lef1 interactions recurring during damage-induced reactivation. Our findings suggest that the interplay of Wnt-Tcf/Lef and TGF-β-Smad3 signaling activates canonical Wnt target promoters in a manner that depends on β-catenin during myoblast proliferation but is independent of β-catenin during MuSC quiescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Self Renewal
  • Cells, Cultured
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism*
  • Mice
  • Satellite Cells, Skeletal Muscle / cytology*
  • Satellite Cells, Skeletal Muscle / metabolism
  • Signal Transduction
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, mouse
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Smad3 Protein
  • Smad3 protein, mouse
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • beta Catenin