Loss of GATA-6 and GATA-4 in Granulosa Cells Blocks
Folliculogenesis, Ovulation, and Follicle Stimulating
Hormone Receptor Expression Leading to Female
Infertility
posted on 2013-11-19, 00:00authored byJill Bennett, Yan-Guang Wu, Jan Gossen, Ping Zhou, Carlos Stocco
Single GATA-6 (G6gcko), GATA-4 (G4gcko), and double GATA-4/6 (G4/6gcko) granulosa cell-specific
knockout mice were generated to further investigate the role of GATA transcription factors in
ovarian function in vivo. No reproductive defects were found in G6gcko animals. G4gcko animals
were subfertile as indicated by the reduced number of pups per litter and the release of significantly
fewer oocytes at ovulation. In marked contrast, G4/6gcko females fail to ovulate and are
infertile. Furthermore, G4/6gcko females had irregular estrous cycles, which correlate with the
abnormal ovarian histology found in unstimulated adult G4/6gcko females showing lack of follicular
development and increased follicular atresia. Moreover, treatment with exogenous gonadotropins
did not rescue folliculogenesis or ovulation in double-knockout G4/6gcko mice. In addition,
ovary weight and estradiol levels were significantly reduced in G4gcko and G4/6gcko animals when
compared with control and G6gcko mice. Aromatase, P450scc, and LH receptor expression was
significantly lower in G4gcko and G4/6gcko mice when compared with control animals. Most prominently,
FSH receptor (FSHR) protein was undetectable in granulosa cells of G4gcko and G4/6gcko.
Accordingly, gel shift and reporter assays revealed that GATA-4 binds and stimulates the activity
of the FSHR promoter. These results demonstrate that GATA-4 and GATA-6 are needed for normal
ovarian function. Our data are consistent with a role for GATA-4 in the regulation of the FSHR gene
and provide a possible molecular mechanism to explain the fertility defects observed in animals
with deficient GATA expression in the ovary.
Funding
National Institutes of Health
Grants R01HD057110 and R21HD066233. The University
of Virginia Center for Research in Reproduction Ligand
Assay and Analysis Core is supported by the Eunice Kennedy
Shriver National Institute of Child Health and Human Development/
National Institutes of Health (SCCPIR) Grant
U54-HD28934.