GATA Factor Function in Trophoblast

Abstract Rodent and Human pregnancies are associated with a hemochorial placentation. Central to the hemochorial placentation are two trophoblast cell types; (i) syncytiotrophoblasts (STBs), which establish an exchange surface for nutrients and gases at the maternal-fetal interface, and (ii) a specialized population of trophoblast cells referred to as invasive trophoblasts in rodents and extravillous trophoblasts (EVTs), in human. Invasive Trophoblasts/EVTs invade into the maternal uterine tissue and modulate uterine cells, including immune cells and endothelial cells to support continuation of pregnancy and proper development of the fetus. Defective development and function of EVTs contribute to early pregnancy loss and pregnancy associated complications such as preeclampsia and intrauterine growth restriction. Our published and unpublished preliminary studies have established that GATA family transcription factors, GATA2 and GATA3, are conserved in trophoblast cells, including in invasive trophoblasts, across mammalian species and are critical regulators for mammalian placentation. The overarching goal of this proposal is to further define GATA factor-mediated transcriptional mechanisms that regulate development and proper function of specialized trophoblast cell types at the maternal-fetal interface and how defects in GATA factor function contribute to pathological pregnancies. Two specific aims are proposed. In Aim 1, We will study mutant rats, and mutant human TSCs, in which GATA2 and GATA3 will be conditionally deleted and utilize state-of-the art genomics approaches to test the hypothesis that GATA2/GATA3 establish conserved transcriptional program to regulate development and function of invasive trophoblast/EVT lineage. In Aim 2, we will test the hypothesis that defective GATA3 function in trophoblast cells contributes to defective placentation in Trisomy 21 pregnancies. We will study placental tissues from chorionic villous biopsies, patient-specific human trophoblast stem cells and mouse models, representing human Trisomy 21, to test this hypothesis. Successful completion of proposed research will advance our knowledge about GATA factor- mediated molecular mechanisms regulating development and function of the invasive trophoblast/EVT cell lineage and whether impairment of those mechanisms could contribute to pathological pregnancies, such as Trisomy 21.