The role of Notch in establishing ovarian interstitial cells

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Project Summary Ovarian dysfunction is one of the leading causes behind women experiencing infertility in the United States. Ovarian diseases and dysfunctions such as polycystic ovarian syndrome, androgen-producing tumors, primary ovarian insufficiency, or hyperandrogenism contribute to infertility in women. Often these diseases result from defects in ovary formation, particularly during fetal life. Formation of the fetal ovary requires the presence of three main cell lineages: the germ cell lineage forms oocytes, the supporting cell lineage becomes granulosa cells, and the interstitial cell lineage contribute to steroidogenic and non-steroidogenic stromal cell populations. Germ cell and supporting cell lineages in the ovary are studied extensively due to the fact that these two cell types form the follicles, the functional unit in the ovary. On the contrary, the interstitial cell lineage is less studied despite that its dysfunction is associated with ovarian diseases. A critical knowledge gap on ovarian interstitial cells is the cellular dynamics necessary for its specification and formation. The main goal of this application is to fill this knowledge gap and lay the foundation for advances in disease diagnosis, treatment, and prevention by using the mouse as the model. Within the applicant’s first year as a post-doctoral fellow in the Yao Laboratory, they discovered a unique population of cells in the ovary that activate Notch and specifically develop into interstitial cells in adulthood indicating that Notch may play a role in ovarian cell development. These findings lead to the central hypothesis of this proposal: Notch activation establishes the interstitial cell lineage in the fetal ovary. AIM 1 will investigate whether ovarian interstitial cell development requires Notch activation. This will be accomplished by using a conditional and inducible genetic mouse model that silences Notch activation in the progenitor interstitial cell population. AIM 2 will test whether ectopic Notch activation will transform the supporting cells into interstitial cells through the use of separate, conditional, and inducible genetic mouse model that specifically targets the supporting cell population. Ovaries from all of the genetic mouse models will be dissected, morphologically analyzed, and subjected to single cell RNA sequencing for analysis. AIM 3 will investigate how supporting cell and interstitial cell populations interact via the Notch pathway to define their unique identity. This will be accomplished by performing single cell sequencing on lineage traced ovaries. This proposal will address the involvement of the Notch activation in interstitial cell fate determination. Knowledge gained from this proposal will provide a better understanding of how embryonic cells gain their progenitor identity and the mechanisms driving ovarian interstitial cell development. With this information, future studies can directly address the impacts of the environment or other stressors on these processes. Finally, these results may be translated to human health risks involving ovarian disease and dysfunction.