GATA Factor Function in Trophoblast

摘要 流产会导致15%-20%的植入确认妊娠终止。大多数流产 发生在怀孕前三个月和滋养层细胞谱系发育缺陷，这是 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，我们对调控滋养层祖细胞的分子机制知之甚少。 植入后早期胚胎的分化和功能。我们已发表的和初步的研究 GATA家族转录因子GATA2和GATA3在滋养层细胞中保守 哺乳动物物种中的祖细胞，是指定和维持滋养层血统的关键调节因子 在哺乳动物早期发育过程中。这项提案的首要目标是进一步界定GATA因素-- 调节特化细胞发育和正常功能的中介转录机制 母胎交界处滋养层细胞类型。 提出了三个具体目标。目标1将研究Gata2/GATA3双敲除(Gata2-/-/GATA3-/-) 小鼠模型和GATA突变大鼠模型检验GATA细胞自主功能假说 在发育中的胎盘的滋养层祖细胞中，决定分化细胞命运的因素是必不可少的。 AIM 2将在发育中的原代滋养层细胞中进行全局基因表达分析 胎盘有或没有GATA突变。目标是检验GATA因素建立的假设 滋养层干/祖细胞与分化滋养层细胞的差异转录回路 从而确定滋养层细胞亚型。 目的3研究GATA对人滋养层细胞基因表达的调节。这个 目的是检验GATA2和GATA3对于维持核心TSC特异性必不可少的假设 包括人类绒毛在内的哺乳动物滋养层祖细胞的转录程序 人胎盘的细胞滋养层细胞(VCTB)祖细胞。我们还将测试怀孕是否与 疾病涉及VCTB中GATA因子介导的基因调控的改变。

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.