Distinct effects of Hippo-YAP/TAZ and YAP/TAZ-TEAD in epithelial maintenance and repair

The maintenance of epithelial homeostasis is essential for preserving tissue architecture and function, and the transcriptional co-activators YAP/TAZ are central to this regulatory network. Although the Hippo-YAP/TAZ-TEAD axis is known to govern epithelial integrity, it remains unclear to what extent Hippo-controlled YAP/TAZ activity overlaps with, or diverges from, YAP/TAZ-TEAD-dependent transcriptional programs in maintaining epithelial homeostasis. Here, we address this question by employing two complementary mouse models: "SuperHippo," which suppresses YAP/TAZ activity through enhanced Hippo pathway engagement, and "TEADi," which selectively disrupts YAP/TAZ-TEAD interactions. Our results revealed that while both models led to increased epithelial thickness in skin epithelial, SuperHippo mice exhibited pronounced epithelial impairment in oral mucosa, and markedly delayed wound healing. In contrast, TEADi mice displayed tissue-specific phenotypes with minimal disruption to oral epithelium integrity or wound repair. These findings indicate that Hippo-mediated YAP/TAZ regulation may extend beyond TEAD-dependent transcription. Our work clarifies the distinct contributions of Hippo-YAP/TAZ signaling and YAP/TAZ-TEAD interaction to epithelial maintenance and provides a basis for the development of therapeutic strategies targeting YAP/TAZ in epithelial disorders.