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

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

Author information

1
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India.
2
Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
3
Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India.
4
Genome Institute of Singapore, Singapore, Singapore.
5
Centre for Cellular and Molecular Biology, Hyderabad 500007, India. jdhawan@ccmb.res.in.

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.

PMID:
30042129
DOI:
10.1126/scisignal.aan3000

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