Snail/Slug-YAP/TAZ Complexes Control Skeletal Stem Cell Self-Renewal and Differentiation

Bone marrow-derived skeletal stem/stromal cell (SSC) self-renewal and function are critical to skeletal development, homeostasis and repair. Nevertheless, the mechanisms controlling SSC behavior, particularly bone formation, remain ill-defined. Using knockout mouse models that target the zinc-finger transcription factors, Snail, Slug or Snail and Slug combined, a regulatory axis has been uncovered wherein Snail and Slug cooperatively control SSC self-renewal, osteoblastogenesis and bone formation. Mechanistically, Snail/Slug regulate SSC function by forming complexes with the transcriptional co-activators, YAP and TAZ, in tandem with the inhibition of the Hippo pathway-dependent regulation of YAP/TAZ signaling cascades. In turn, the Snail/Slug-YAP/TAZ axis activates a series of YAP/TAZ/TEAD and Runx2 downstream targets that control SSC homeostasis and osteogenesis. Together, these results demonstrate that SSCs mobilize Snail/Slug-YAP/TAZ complexes to control stem cell function.