University of Illinois Chicago
Browse

Loss of GATA-6 and GATA-4 in Granulosa Cells Blocks Folliculogenesis, Ovulation, and Follicle Stimulating Hormone Receptor Expression Leading to Female Infertility

Download (1.64 MB)
journal contribution
posted on 2013-11-19, 00:00 authored by Jill 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.

History

Publisher Statement

This is a copy of an article published in Endocrinology © 2012 Endocrine Society. endo.endojournals.org/ doi: 10.1210/en.2011-1969

Publisher

Endocrine Society

Language

  • en_US

issn

0013-7227

Issue date

2012-05-01

Usage metrics

    Categories

    No categories selected

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC