Sustained YAP1 signaling alters the fate of lutein and Müllerian mesenchymal cells in mice
Recent reports have suggested that the Hippo intracellular signaling pathway is required for homeostasis in a variety of tissues, including the ovary and female reproductive tract.   To further define the role of the Hippo effector YAP1 in the female reproductive system, transgenic mouse models were designed to direct the expression of a dominant stable mutant of YAP1, termed YAP5SA, to the granulosa cells of antral follicles (R26YAP5SA;CYP19-cre) and Müllerian mesenchymal cells (R26YAP5SA;Amhr2cre/+).  Unexpectedly, YAP5SA expression in the ovaries of R26YAP5SA;CYP19-cre mice was not detected in granulosa cells, but rather in a subset of lutein cells.  This caused the lutein cells to transdifferentiate into cells having the morphologic and functional properties of myofibroblasts, including collagen deposition.  These coalesced into roughly spherical lesions that persisted in the ovaries, but did not interfere with ovarian function or fertility.  Seminiferous tubule-like structures also formed in the ovaries of adult R26YAP5SA;CYP19-cre mice, containing SOX9-positive Sertoli-like cells but no germ cells.  Although multi-lineage transdifferentiation had been reported in mice lacking the Hippo kinases Lats1 and -2 in their granulosa cells, comparative RNAseq analyses of granulosa cells expressing YAP5SA vs granulosa cells lacking Lats1/2 showed few similarities in transcriptome alterations.  R26YAP5SA;Amhr2cre/+ mice had severe developmental defects of their uterine horns and ovaries, which were attributed to transdifferentiation of Müllerian mesenchymal cells into myofibroblasts during embryogenesis.  Together, these results indicate that sustained YAP1 signaling induces transdifferentiation in lutein and Müllerian mesenchymal cells, and further underscores the role of Hippo signaling in the maintenance of their fates. Overall design: Primary culture of mouse preovulatory granulosa cells infected with Adenovirus-Cre (or  Adenovirus-eGFP as control) during 18h.