Fibroblast-specific deletion of Yap/Taz impairs mouse postnatal dermal development by diminishing collagenous matrix

The transcriptional coactivators YAP (yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are key regulators of cell proliferation, apoptosis, and differentiation, thereby maintaining tissue homeostasis and controlling organ size. Although their roles in epithelial cancers and fibrosis are well-established, their involvement in the physiological regulation of the dermal extracellular matrix (ECM) by fibroblasts is less understood. In this study, we investigated the role of Yap/Taz during postnatal development of the dermal ECM. During postnatal growth, mouse skin steadily undergoes significant surface expansion. Postnatal deletion of Yap/Taz in dermal fibroblasts, the primary cells responsible for dermal ECM homeostasis, significantly impairs dermal ECM maturation, as evidenced by marked deficiencies in collagen expression, deposition, and organization. Isolated fibroblasts from Yap/Taz-knockout mice show reduced expression of Yap/Taz target genes (Ccn1, Ccn2, Col1a1), which is rescued by reintroduction of active Yap/Taz. RNA sequencing, spatial transcriptomics, and proteomics of Yap/Taz-knockout skin reveal substantial downregulation of ECM-related genes, including type I (Col1a1, Col1a2) and type III (Col1a3) collagens, which together constitute more than 90% of the skin's collagen content. Mechanistically, deletion of Yap/Taz impairs mouse dermal maturation, at least in part, through the suppression of TGF-β/Smad signaling, the primary pathway governing fibroblast collagen synthesis. These findings demonstrate that YAP/TAZ are essential for postnatal dermal ECM homeostasis.