Oocyte stage-specific role of ERβ in primordial follicle activation

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SUMMARY In mammalian ovaries, a fixed number of primordial follicles that are formed during the fetal or early neonatal period serve as the source of mature oocytes for the entire reproductive lifespan. Uncontrolled or excessive activation of primordial follicles leads to the depletion of the ovarian reserve, resulting in ovulatory dysfunction. We demonstrated that estrogen receptor β (ERβ) plays a gatekeeping role during primordial follicle activation (PFA). In both the rat and the mouse, the absence of ERβ results in increased numbers of primordial follicles being activated and developing into primary follicles. In a conditional knockout mouse that lacks ERβ in oocytes starting from the primordial follicle stage, we detected excessive activation of primordial follicles similar to that of Erβnull mutants. Based on this novel observation, we hypothesize that ERβ regulation of PFA is mediated by its transcriptional function in the oocytes of primordial or primary follicles. However, it remains unclear if the regulatory mechanism of ERβ is restricted to the primordial follicles or if it can function in activated primary follicles. Also, our observations cannot exclude a potential role for ERβ in follicular granulosa cells. In this study, we propose to define oocyte stage-specific roles of ERβ in the regulation of PFA. Using follicular stage-specific conditional ERβ knockout mice, we will: 1) determine the role of ERβ in controlling PFA in both primordial and activated oocytes, 2) assess the ovarian phenotypes following oocyte stage-specific ERβ depletion, 3) perform single cell transcriptome analyses to identify the ERβ-regulated oocyte genes involved in PFA, and 4) identify any granulosa-specific genes that are differentially impacted due to oocyte-specific depletion of ERβ. ERβ is a ligand activated nuclear receptor that has well-characterized selective ligands approved for use in clinical trials. Although it is the predominant estrogen receptor in the ovary, ERβ has never been targeted to treat ovarian dysfunction. The results of the proposed research will provide insight into how the molecular targeting of ERβ might enhance our efforts to extend female reproductive longevity and improve existing assisted reproductive technologies.