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Sustained YAP1 signaling alters the fate of lutein and Müllerian mesenchymal cells in mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE281696 | GEO | 2025/03/31

REPOSITORIES: GEO

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Project description:The small G-protein KRAS is crucial for mediating gonadotropin-induced events associated with ovulation. However, constitutive expression of KrasG12D in granulosa cells disrupted normal follicle development leading to the persistence of abnormal follicle-like structures containing non-mitotic cells. To determine what factors mediate this potent effect of KrasG12D, gene profiling analyses were done. We also analyzed KrasG12D;Cyp19-Cre and KrasG12D;Pgr-Cre mutant mouse models that express Cre prior to or after the initiation of granulosa cell differentiation, respectively. KrasG12D induced cell cycle arrest in granulosa cells of the KrasG12D;Cyp19-Cre mice but not in the KrasG12D;Pgr-Cre mice, documenting the cell context specific effect of KrasG12D. Expression of KrasG12D silenced the Kras gene, reduced cell cycle activator genes and impaired expression of granulosa cell and oocyte specific genes. Conversely, levels of PTEN and phosphorylated p38MAPK increased markedly in the mutant granulosa cells. Because disrupting Pten in granulosa cells leads to increased proliferation and survival, Pten was disrupted in the KrasG12D mutant mice. The Pten/Kras mutant mice were infertile but lacked GCTs. By contrast, the Ptenfl/fl;KrasG12D;Amhr2-Cre mice developed aggressive ovarian surface epithelial (OSE) cell tumors that did not occur in the Ptenfl/fl;KrasG12D;Cyp19-Cre or Ptenfl/fl;KrasG12D;Pgr-Cre mouse strains. These data document unequivocally that Amhr2-Cre is expressed in and mediates allelic recombination of oncogenic genes in OSE cells. That KrasG12D/Pten mutant granulosa cells do not transform but rather undergo cell cycle arrest indicates that they resist the oncogenic insults of Kras/Pten by robust self-protecting mechanisms that silence the Kras gene and elevate PTEN and phospho-p38MAPK. Experiment Overall Design: Whole ovaries were collected from 26-day-old wild type mice, 26-day-old K-ras conditional mutant mice and 3-month-old K-ras conditional mutant mice. The gene expression profiles of these samples were compared using microarray method.

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Sustained YAP1 signaling alters the fate of lutein and Müllerian mesenchymal cells in mice

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