The transcription factor Lef1 switches partners from {beta}-catenin to Smad3 during muscle stem cell 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 s...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news