The CalcR-PKA-Yap1 Axis is Critical for Maintaining Quiescence in Muscle Stem Cells

Quiescence is a fundamental property of adult stem cells. Recent evidence indicates that quiescence is not a default state but requires active signaling that prevents accidental or untimely activation of stem cells. The calcitonin receptor (CalcR) is critical for sustaining quiescence in muscle satellite (stem) cells (MuSCs). However, the molecular mechanisms, by which CalcR signaling regulates quiescence in MuSCs, are enigmatic. Here, we demonstrate that transgenic expression of the catalytic domain of PKA restores quiescence of CalcR-mutant MuSCs and delays MuSC activation. Mechanistically, CalcR-activated PKA phosphorylates Lats1/2, the main effector of Hippo-signaling, thereby inhibiting nuclear accumulation of Yap1, which prevents expression of Hippo-target genes including cell cycle-related molecules. Importantly, genetic inactivation of Yap1 in CalcR-mutant MuSCs reinstates quiescence in CalcR-mutant MuSCs indicating that the CalcR-PKA-Lats1/2-Yap1 axis plays a critical role for sustaining MuSC quiescence.