Research ArticleStem Cells

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

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Science Signaling  24 Jul 2018:
Vol. 11, Issue 540, eaan3000
DOI: 10.1126/scisignal.aan3000

Muscle stem cells swap coactivators

After birth, skeletal muscle stem cells (MuSCs) transition from a proliferative to a quiescent state. These quiescent stem cells, also known as satellite cells, retain the ability to self-renew and, upon activation, re-enter the cell cycle to generate myoblasts for muscle repair. The entry of MuSCs into quiescence is characterized by the expression of target genes that are activated by the Tcf and Lef (Tcf/Lef) family of transcription factors. Aloysius et al. found that, although Tcf/Lef transcription factors promoted gene expression by cooperating with β-catenin in response to Wnt signaling in proliferating myoblasts, β-catenin was not required for the induction of Tcf/Lef target genes during quiescence. Instead, Lef1 partnered with the transcriptional coactivator Smad3. Smad3 mediates transcriptional responses to transforming growth factor–β (TGF-β) signaling, implicating cross-talk between the Wnt and TGF-β pathways in controlling MuSC quiescence.


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.

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