ABSTRACT: Recent reports suggest that the Hippo signaling pathway influences ovarian follicle development; however, its exact roles remain unknown. Here, we examined the ovarian functions of the Hippo kinases large tumor suppressors (LATS)1 and 2, which serve to inactivate the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Inactivation of Lats1/2 in murine granulosa cells either in vitro or in vivo resulted in a loss of granulosa cell morphology, function, and gene expression. Mutant cells further underwent changes in structure and gene expression suggestive of epithelial-to-mesenchymal transition and transdifferentiation into multiple lineages. In vivo, granulosa cell-specific loss of Lats1/2 caused the ovarian parenchyma to be mostly replaced by bone tissue and seminiferous tubule-like structures. Transdifferentiation into Sertoli-like cells and osteoblasts was attributed in part to the increased recruitment of YAP and TAZ to the promoters of sex-determining region Y box 9 and bone γ-carboxyglutamate protein, key mediators of male sex determination and osteogenesis, respectively. Together, these results demonstrate for the first time a critical role for Lats1/2 in the maintenance of the granulosa cell genetic program and further highlight the remarkable plasticity of granulosa cells.-Tsoi, M., Morin, M., Rico, C., Johnson, R. L., Paquet, M., Gévry, N., Boerboom, D. Lats1 and Lats2 are required for ovarian granulosa cell fate maintenance.
