Integrin signalling regulates YAP and TAZ to control skin homeostasis

The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here we show that YAP and TAZ are nuclear localised in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent Integrin-Src signalling is a key determinant of YAP/TAZ nuclear localisation in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. In contrast, columnar epithelia differentiate an apical domain that recruits CRB3, MERLIN, KIBRA and SAV to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib. (CYR61, CTGF), and EGFR ligands (AREG), we propose that a positive feedback loop drives basal layer stem/progenitor cell identity, and that this loop is broken when daughter cells lose contact with the basement membrane and differentiate – forming a bistable system of cell fate determination. Our findings provide an explanation