Control of skeletal morphogenesis by the Hippo-YAP/TAZ pathway.

The Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, , / double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, , cartilage-specific knockout of / does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of or knockout of / do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include , and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation , possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation , and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.