GATA4 and GATA6 are Essential for Folliculogenesis, Ovulation, Corpus Luteum Function & Female Fertility

Follicle selection, ovulation, luteinization and atresia are crucial for normal ovarian function. Several genes involved in these processes contain within their regulatory elements the WGATAR motif, which is recognized by the GATA family of transcription factors. To investigate the role of GATA in ovarian granulosa cell function in vivo, GATA4 (G4gcko), GATA6 (G6gcko) and double GATA4/6 (G4/6gcko) conditional knockout mice were generated. No reproductive defects were found in G6gcko animals. G4gcko animals are subfertile and release significantly fewer oocytes at ovulation. G4/6gcko females are infertile due to a halt in folliculogenesis at the early antral stage, which leads to ovulation failure, estrous cycle irregularities, low estradiol levels, and follicular atresia. The defects in folliculogenesis are, at least in part, caused by a reduction of FSH receptor (FSHR) in granulosa cells of G4gcko and G4/6gcko.Furthermore, we showed that GATA4 binds and stimulates the activity of the FSHR promoter. To uncover other potential targets of GATA in granulosa cells, we performed microarray analysis on control and GATA4/6-null granulosa cells. The results showed that genes involved in hormone metabolism, extracellular matrix, IGF1 activity and apoptosis are affected by the lack of GATA4/6 expression. The lack of follicle development found in G4/6gcko animals precluded studies to examine the role of GATA in luteal cells where they are also highly expressed. To overcome this limitation, conditional knockout animals in which the GATA4 and GATA6 genes were deleted at ovulation (G4/6prko) were generated. G4/6prko animals were infertile despite that they cycle, ovulate, and form corpora lutea normally. However, the corpora lutea of the G4/6prko mice produce and release extremely low levels of progesterone, which may explain their infertility. In fact, implantation was partially rescued by exogenous progesterone. Noteworthy, the oviducts and uteri of G4/6prko. These results demonstrate that GATA4 and GATA6 are required for the normal progress of folliculogenesis and luteal progesterone synthesis. The regulation of the FSHR expression and the diversity of pathways affected by the knockdown of GATA factors underscores the importance these factors in granulosa and luteal cell function.