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Cellular and molecular mechanisms underlying granulosa cell tumor induced by constitutively activated TGFB signaling

ABSTRACT: Mice harboring constitutively activated TGFβ signaling (TGFBR1-CA) develop ovarian GCTs that phenocopy the hormonal and several molecular characteristics of human GCTs. The goal of this study is to determine molecular alterations in the ovary upon TGFβ signaling activation. We performed Next-generation sequencing (NGS) analysis of ovaries from TGFBR1-CA mice and age-matched controls during tumor formation

ORGANISM(S): Mus musculus

PROVIDER: GSE187015 | GEO | 2022/05/18

REPOSITORIES: GEO

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Project description:Transforming growth factor β (TGFβ) signaling regulates multifaceted reproductive processes via its transmembrane receptor complex-associated machinery. It has been shown that the type 1 receptor of TGFβ (TGFBR1) is indispensable for female reproductive tract development, pregnancy success, and fertility. However, the role of TGFβ signaling in decidual development and function remains poorly defined. Our objective is to determine the impact of uterine-specific deletion of Tgfbr1 on the differentiation of endometrial stromal cells in pregnant mice, with a focus on the cellular and molecular properties of the decidua. An approach combining histological and immunohistochemical analyses, quantitative PCR, western blot, and RNA-sequencing was utilized. Our results show that decidual development is altered in TGFBR1 conditionally depleted uteri, substantiated by downregulation of genes associated with inflammatory response and uterine natural killer cell abundance, reduced presence of non-decidualized fibroblasts in the antimesometrial region, and impaired decidual cell differentiation. Notably, conditional ablation of TGFBR1 results in the formation of decidua containing more abundant alpha smooth muscle actin (ACTA2)-positive cells at the peripheral region of the antimesometrial side versus controls. This finding is corroborated by upregulation of a subset of smooth muscle marker genes in Tgfbr1 conditionally-deleted decidua. The abnormal cell differentiation is accompanied with increased cell proliferation and enhanced decidual ERK1/2 signaling upon decidual regression. In summary, this study has identified an important role of TGFBR1 in decidual cell differentiation by revealing that conditional ablation of TGFBR1 in the uterus profoundly impacts the cellular and molecular properties of the decidua. Our results suggest that TGFBR1 is required for the development of an integral decidua, a transient but crucial structure that supports embryo development.

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Cellular and molecular mechanisms underlying granulosa cell tumor induced by constitutively activated TGFB signaling

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