FXR maintains primordial follicle dormancy via regulating FoxO3 expression

Area of Science:

• Reproductive biology
• Endocrinology
• Molecular genetics

Background:

• Farnesoid X receptor (FXR), a nuclear receptor, is found in the ovary, but its reproductive role is unknown.
• Ovarian reserve, crucial for female fertility, is maintained by regulating primordial follicle activation and dormancy.

Purpose of the Study:

• To investigate the role of FXR in regulating ovarian reserve maintenance.
• To elucidate the molecular mechanisms by which FXR influences primordial follicle activation.

Main Methods:

• Utilized a novel FXR knockout (FXR-KO) mouse model.
• Analyzed ovarian follicle pools and primordial follicle activation markers (e.g., FOXO3) in neonatal ovaries.
• Investigated FXR's direct binding to the FoxO3 promoter using molecular techniques.
• Performed in vitro studies using granulosa cells treated with FXR agonists.

Main Results:

• FXR-KO mice displayed increased oocyte ovulation and a larger secondary follicle pool, indicating enhanced primordial follicle recruitment.
• Neonatal FXR-KO ovaries showed accelerated primordial follicle activation, linked to increased Forkhead box O3 (FOXO3) nuclear exclusion.
• FXR activation suppressed primordial follicle activation in wild-type ovaries; FXR directly upregulated FoxO3 expression transcriptionally.
• In vitro, FXR activation in granulosa cells increased cell cycle inhibitors and reduced proliferation, suggesting a role in maintaining follicle dormancy.

Conclusions:

• FXR is identified as a novel regulator of ovarian reserve maintenance.
• FXR restrains granulosa cell differentiation and promotes oocyte quiescence, thereby preserving primordial follicle dormancy.
• FXR represents a potential pharmacological target for modulating reproductive lifespan and fertility management.