Mechanical instability of adherens junctions overrides intrinsic quiescence of hair follicle stem cells

Vinculin, a mechanotransducer associated with both adherens junctions (AJs) and focal adhesions (FAs), plays a central role in force transmission through cell-cell and cell-substratum contacts. We generated the conditional knockout (cKO) of vinculin in murine skin that results in the loss of bulge stem cell (BuSC) quiescence and promotes continual cycling of the hair follicles. Surprisingly, we find that the AJs in vinculin cKO cells are mechanically weak and impaired in force generation despite increased junctional expression of E-cadherin and α-catenin. Mechanistically, we demonstrate that vinculin functions by keeping α-catenin in a stretched/open conformation, which in turn regulates the retention of YAP1, another potent mechanotransducer and regulator of cell proliferation, at the AJs. Altogether, our data provide mechanistic insights into the hitherto-unexplored regulatory link between the mechanical stability of cell junctions and contact-inhibition-mediated maintenance of BuSC quiescence. [Display omitted] •cKO of vinculin (VCL) in skin results in loss of bulge stem cell quiescence•VCL-KO cells are impaired in force generation, resulting in mechanically weak AJs•VCL keeps α-catenin in a stretched/open conformation that localizes YAP1 to AJs•Mechanically stable AJs maintain of stem cell quiescence via contact inhibition Biswas et al. identify a causal link between loss of mechanically stable adherens junctions (AJs) and the failure to maintain bulge stem cell quiescence in cKO of vinculin (VCL) in the skin. Mechanistically, VCL keeps α-catenin in a stretched/open conformation that sequesters the potent cell-cycle regulator YAP1 to the junctions.