Hippo Signaling Effector and Placentation

摘要 早期妊娠丢失影响15-20%的经确认的妊娠。大多数妊娠失败 发生在妊娠早期，滋养层祖细胞发育缺陷，这确保胚胎 着床和胎盘形成是早期流产的主要原因之一。然而，我们有一个贫穷的 了解调节滋养层祖细胞自我更新，分化和 在早期着床后胚胎中发挥作用。我们发表的和初步的研究表明，河马信号 效应转录因子TEAD 4在哺乳动物的滋养层祖细胞中是保守的， 在早期哺乳动物发育过程中，滋养层细胞是一种重要的调节因子，对滋养层细胞谱系的形成和维持起着重要作用。的 该提案的首要目标是进一步定义TEAD 4介导的保守分子机制， 在植入后胎盘中特异性参与调节滋养层祖细胞的自我更新和分化 发展此外，我们还将测试这些机制的改变是否与复发性 妊娠丢失（RPL）。 提出了三个具体目标。目的1将研究突变小鼠模型，以检验TEAD 4 调节滋养层干细胞样祖细胞（TSPC）的自我更新在早期植入后胚胎。 目的2验证TEAD 4在谱系特异性滋养细胞中的细胞自主功能 祖细胞确保分化的滋养层细胞的适当发育和母胎界面的形成。 在目标3中，我们将测试TEAD 4在人原代细胞滋养层（CTB）和CTB-1中的功能重要性。 衍生的人滋养层干细胞（TSC）。我们还将招募已知有反复妊娠史的患者 损失（RPL）以分离CTB并建立患者特异性TSC。目的是检验TEAD 4调节 CTB祖细胞在发育中的人胎盘中的自我更新和TEAD 4的功能缺陷是分子原因 不明原因（特发性）RPL的子集。

Abstract Early pregnancy loss affects 15-20% of implantation-confirmed pregnancies. Majority of these pregnancy losses occur during first trimester and defective development of trophoblast progenitors, 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 self-renewal, differentiation and function in early postimplantation embryos. Our published and preliminary studies establish that hippo signaling effector, transcription factor TEAD4 is conserved in trophoblast progenitors across mammalian species and is a critical regulator to specify and maintain the trophoblast cell lineage during early mammalian development. The overarching goal of this proposal is to further define TEAD4-mediated conserved molecular mechanisms that are specifically involved in regulating trophoblast progenitor self-renewal and differentiation during post-implantation placenta development. In addition, we will also test whether alteration of those mechanisms is associated with recurrent pregnancy loss (RPL). Three specific aims are proposed. Aim 1 will study mutant mouse models to test the hypothesis that TEAD4 regulates trophoblast stem-like progenitor cell (TSPC) self-renewal in early postimplantation embryos. Aim 2 will test the hypothesis that cell-autonomous function of TEAD4 in lineage-specific trophoblast progenitors ensures proper development of differentiated trophoblast cells and formation of the maternal-fetal interface. In Aim 3, we will test functional importance of TEAD4 in human primary cytotrophoblasts (CTBs) and CTB- derived human trophoblast stem cells (TSCs). We will also recruit patients with known history of recurrent pregnancy loss (RPL) to isolate CTBs and establish patient-specific TSCs. The goal is to test the hypothesis that TEAD4 regulates self-renewal of CTB progenitors in a developing human placenta and defective function of TEAD4 is the molecular cause for a subset of unexplained (idiopathic) RPLs.