Grant: Operating Grant

We are studying the role of a family of transcription factors (proteins that participate in turning genes on or off), called GATA proteins, known for their essential function in regulating the development and function of blood cells, the heart, and the immune system. We have shown that GATA factors are prominently expressed in the reproductive organs (testis and ovary). GATA4 is required for early gonad development in both sexes; without this factor abnormalities such as ambiguous genital development occur. GATA4 also appears to be important for function of the mature gonad since in the absence of GATA4, male and female infertility can result. The objective of our research is to define the mechanism of action of GATA4 (i.e., how it accomplishes its functions) and to understand how its expression and activity is regulated in cells of the testis and ovary. To understand GATA4 function is to understand what genes it regulates. We inactivated GATA4 in steroid (testosterone)-producing cells and identified new GATA4 regulated genes involved in steroid hormone production. Our research proposes to investigate how GATA4 controls these critical genes that are essential not only for establishing male/female sex differences during gestation and puberty but also fertility in adulthood. Since some of these new targets are also associated with hormone-dependent pathologies of the skin such as acne and male pattern baldness, it opens the door to investigating the role of GATA4 in these prevalent medical conditions. GATA4 gene mutations are known to affect human health; one recently reported GATA4 mutation has been associated with abnormal genital development in men. Our studies propose to study the effects of this and other novel human GATA4 mutations through studies in cells and by recreating the mutations in mice.