Estrogens profoundly influence the physiology and pathology of reproductive and other tissues. Therefore, much emphasis has been placed on delineating the mechanisms underlying regulation of estrogen synthesis. Circulating levels of estradiol in women are controlled by the pituitary gonadotropin follicle stimulating hormone (FSH), which regulates transcription of the aromatase gene (CYP19A1) in ovarian follicles. Previous studies have focused on two downstream effectors, cAMP and the orphan nuclear receptor SF1 (NR5A1).
Herein, we present new evidence for beta-catenin (CTNNB1) as an essential transcriptional regulator of CYP19A1 in granulosa cells. Beta-catenin enhances FSH induction of select steroidogenic enzyme mRNAs, including Cyp19a1, via functional interactions with SF1. Additionally, beta-catenin associates with the endogenous gonad-specific CYP19A1 promoter, and modulates its activation by FSH and cAMP-dependent signaling cascades.
Preliminary data also indicate that Tcf/Lef family members are expressed in a stage-specific manner in the ovary. FSH, acting through elevation of intracellular cAMP, stimulates beta-catenin/TCF-dependent transcription in immature granulosa cells. However, in contrast to SF1, disruption of the functional interaction between beta-catenin and TCF7L2 differentially affects Cyp19a1 induction in primary granulosa cells and those derived from a human granulosa cell tumor. Thus, beta-catenin/TCF interactions may normally limit Cyp19a1 in granulosa cells, but in tumorigenic states could contribute to excess estrogen synthesis. Finally, the ability of cAMP cascades to regulate beta-catenin-dependent transcription appears to involve novel mechanisms un-preceded by beta-catenin accumulation or changes in sub-cellular localization.
Together, these data provide the first demonstration that beta-catenin is essential for FSH/cAMP regulated gene expression in the ovary, exerting its effects through SF1, and potentially TCF7L2. Our results identify a central and previously unappreciated role for beta-catenin in estrogen biosynthesis, and predict a potential broader role in other aspects of follicular maturation and tumorigenesis.