Coordinated activation and repression of genes are essential for the normal progress of the ovarian cycle. Ovarian granulosa cells express high levels of the transcription factors GATA-4 and GATA-6. In cell cultures, these transcription factors were shown to play key roles in the expression of enzymes involved in steroidogenesis. We have demonstrated in several recently published papers that GATA-4 is critical for the production of estradiol, which is essential for granulosa cell proliferation and follicle maturation. In addition, the finding that low expression of GATA-4 is associated with follicular cell death suggests that this factor also plays a survival role in the ovary. Because GATA-4 and GATA-6 null mice are embryonic lethal, the ultimate role of GATA in ovarian function remains unknown. This study is therefore designed to determine the physiological role of GATA-4 and GATA-6 in ovarian steroidogenesis, follicular development, and female fertility.
The specific aims of this study are: 1- To generate ovarian-specific GATA-4 and GATA-6 null mice in order to find out the explicit roles of these transcription factors in the ovary in vivo. The Cre-lox technology will be used to delete part of the coding region of GATA-4, GATA-6, or their combination. We expect these mice to have severe defects in steroid production and in follicular development. 2- To determine the effect of GATA-4 and GATA-6 deletion on ovarian cells in vitro. Granulosa cells lacking GATA-4, GATA-6, or both will be used to examine the specific roles of these factors in steroidogenesis, cell proliferation, granulosa-cell hormone response, and gene expression. 3- To identify those genes that are regulated by GATA-4 and GATA-6 in fully functional ovaries in vivo, we will use ChIP-on-chip assays. All the results obtained to date indicate that GATA-4 and GATA-6 may play a crucial role in the normal function of the ovary. We expect from this investigation to clearly define the function of GATA-4 and GATA-6 in the steroidogenic capacity and growth of granulosa cells, to determine whether GATA-4 and GATA-6 have redundant effects on these cells, and to identify GATA-4 and GATA-6 target genes in the ovary. This study will not only provide critically important information on the regulatory mechanism underlying normal ovarian function but also may shed light on ovarian diseases due to improper granulosa cell function such as granulosa cell tumors and infertility.

Public Health Relevance

The roles of the transcription factors GATA-4 and GATA-6 in folliculogenesis and fertility will be addressed. These studies will contribute to better understanding of the cellular and molecular mechanisms that control ovarian function and improve our knowledge of the etiology of ovarian diseases such as granulosa cell tumors and infertility.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Taymans, Susan
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University of Illinois at Chicago
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Baumgarten, Sarah C; Armouti, Marah; Ko, CheMyong et al. (2017) IGF1R Expression in Ovarian Granulosa Cells Is Essential for Steroidogenesis, Follicle Survival, and Fertility in Female Mice. Endocrinology 158:2309-2318
Convissar, Scott; Armouti, Marah; Fierro, Michelle A et al. (2017) Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells. Reproduction 154:745-753
Baumgarten, Sarah C; Convissar, Scott M; Zamah, A Musa et al. (2015) FSH Regulates IGF-2 Expression in Human Granulosa Cells in an AKT-Dependent Manner. J Clin Endocrinol Metab 100:E1046-55
Convissar, Scott M; Bennett, Jill; Baumgarten, Sarah C et al. (2015) GATA4 and GATA6 Knockdown During Luteinization Inhibits Progesterone Production and Gonadotropin Responsiveness in the Corpus Luteum of Female Mice. Biol Reprod 93:133
Baumgarten, Sarah C; Convissar, Scott M; Fierro, Michelle A et al. (2014) IGF1R signaling is necessary for FSH-induced activation of AKT and differentiation of human Cumulus granulosa cells. J Clin Endocrinol Metab 99:2995-3004
Bennett, Jill; Baumgarten, Sarah C; Stocco, Carlos (2013) GATA4 and GATA6 silencing in ovarian granulosa cells affects levels of mRNAs involved in steroidogenesis, extracellular structure organization, IGF-I activity, and apoptosis. Endocrinology 154:4845-58
Zhou, Ping; Baumgarten, Sarah C; Wu, Yanguang et al. (2013) IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells. Mol Endocrinol 27:511-23
Wu, Yanguang; Baumgarten, Sarah C; Zhou, Ping et al. (2013) Testosterone-dependent interaction between androgen receptor and aryl hydrocarbon receptor induces liver receptor homolog 1 expression in rat granulosa cells. Mol Cell Biol 33:2817-28
Stocco, Carlos (2012) The long and short of the prolactin receptor: the corpus luteum needs them both! Biol Reprod 86:85
Stocco, Carlos (2012) Tissue physiology and pathology of aromatase. Steroids 77:27-35

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