Analysis of knockout mice reveals critical female-specific roles for the Hippo pathway component PTPN14

The Hippo pathway regulates many physiological processes, including development, tumor suppression, and wound healing. One understudied Hippo pathway component is PTPN14, an evolutionarily conserved tyrosine phosphatase that inhibits YAP/TAZ. Although it is an established tumor suppressor, PTPN14's role in tissue homeostasis has remained unclear. We thus generated <i>Ptpn14</i>-deficient mice and found that only ∼60% of <i>Ptpn14</i> ^-<i>/</i>- mice survived postnatally, highlighting the importance of PTPN14 for viability while also enabling the discovery of PTPN14 physiological functions. <i>Ptpn14</i> ^-<i>/</i>- mice developed debilitating corneal lesions and the uterus defect hydrometra, as well as heart and kidney abnormalities. <i>Ptpn14</i> deficiency precipitated an impaired injury response in the cornea and dysregulated YAP signaling in both the uterus and the cornea. Notably, these phenotypes were female-specific, revealing sexually dimorphic Hippo pathway function through PTPN14. Finally, analysis of human <i>PTPN14</i> variants suggested that PTPN14's essential roles are conserved in humans, underscoring the importance of our insights for designing therapies to improve women's health.