GATA Factor Function in Trophoblast

摘要 流产导致15-20%的流产确认妊娠终止。大多数流产 发生在怀孕的前三个月和滋养层细胞谱系的发育缺陷， 确保胚胎着床和胎盘形成，是导致早期妊娠丢失的主要原因之一。 然而，我们对调节滋养层祖细胞的分子机制了解甚少， 分化和功能在早期植入后胚胎。我们已发表和初步研究 确定加塔家族转录因子GATA 2和GATA 3在滋养层中是保守 哺乳动物物种的祖细胞，是指定和维持滋养层谱系的关键调节因子 在哺乳动物的早期发育中。本提案的首要目标是进一步定义加塔因素- 介导的转录机制，调节发育和正常功能的专门 滋养层细胞类型在母胎界面。 提出了三个具体目标。目标1将研究Gata 2/Gata 3双敲除（Gata 2-/-/Gata 3-/-） 小鼠模型和GATA突变的大鼠模型来检验加塔的细胞自主功能 这些因子对于在发育中的胎盘的滋养层祖细胞中建立分化的细胞命运是必需的。 目的2将在发育中的原代滋养层细胞中进行全面的基因表达分析。 有或无加塔突变的胎盘。目的是检验加塔因素建立的假设 滋养层干/祖细胞与分化的滋养层细胞中的差异转录电路， 从而确定滋养层亚型。 目的3研究GATA对人滋养层细胞基因表达的调控。的 目的是检验GATA 2和GATA 3对维持核心TSC特异性 在哺乳动物物种的滋养层祖细胞中的转录程序，包括人类绒毛 人胎盘的细胞滋养层（vCTB）祖细胞。我们还将测试是否与怀孕有关 疾病涉及vCTB中改变的加塔因子介导的基因调控。

Abstract Miscarriage causes termination of 15-20% of implantation-confirmed pregnancies. Majority of miscarriages occur during the first trimester of pregnancy and defective development of trophoblast cell lineage, which assures embryo implantation and placentation, is one of the leading causes for early pregnancy loss. However, we have a poor understanding of molecular mechanisms that regulate trophoblast progenitor differentiation and function in early post-implantation embryos. Our published and preliminary studies establish that GATA family transcription factors, GATA2 and GATA3, are conserved in trophoblast progenitors across mammalian species and are critical regulators to specify and maintain trophoblast lineage during early mammalian development. 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. Three specific aims are proposed. Aim 1 will study a Gata2/Gata3 double knockout (Gata2-/-/Gata3-/-) mouse model and GATA-mutated rat models to test the hypothesis that cell-autonomous functions of GATA factors are essential to establish differentiated cell-fate in the trophoblast progenitors of a developing placenta. Aim 2 will perform global gene expression analyses in primary trophoblast cells of developing placenta with or without GATA mutations. The goal is to test the hypothesis that GATA factors establish differential transcriptional circuitry in trophoblast stem/progenitor cells vs. differentiated trophoblast cells, thereby specifying trophoblast subtypes. Aim 3 will study GATA-mediated regulation of gene expression in human trophoblast cells. The objective is to test the hypothesis that GATA2 and GATA3 are essential to maintain a core TSC-specific transcriptional program in trophoblast progenitors across mammalian species, including human villous cytotrophoblast (vCTB) progenitors of a human placenta. We will also test whether pregnancy associated disorders involve altered GATA factor-mediated gene regulation in vCTBs.