Analysis of Trophoblast Cell Motility

提供了 胚胎植入子宫和随后的胎盘形成是独特和关键的 哺乳动物的发育特征。它们是由滋养层细胞介导的，滋养层细胞产生于 胚泡的上皮滋养外胚层细胞。在植入时，它们转化为侵入性细胞 其取代并吞噬子宫上皮细胞，以便穿透子宫基质， 与母体血液供应的血管连接。细胞行为与 上皮滋养外胚层转化为运动的滋养层，随后转化为内皮细胞， 滋养层巨细胞对于着床和胎盘形成的成功以及最终对于 胚胎本身的发育。然而，我们对这些细胞中关键细胞事件的理解， 这两个过渡，以及对它们的监管，仍然是相当初级的。 在这项提议中，中心假设是，在运动行为的调节变化， 滋养层细胞是它们在着床和胎盘形成中发挥功能的基础。拟议的实验 重点关注滋养层巨细胞分化的两个方面：第一，上皮滋养外胚层向 第二，从运动的滋养层到滋养层巨细胞的转变。的发作 滋养外胚层的运动性由氨基酸，特别是亮氨酸和精氨酸的可用性调节。 由这些氨基酸激活的信号机制在调节肿瘤发生中的功能 将描述滋养外胚层的侵入活性，特别是关于硝酸盐的作用。 氧化物和多胺合成。植入后，滋养层细胞形成复杂的吻合网络， - 卵黄囊胎盘的窦，因为它们经历终末分化为滋养层巨细胞。这 该过程与运动性和细胞形状的进一步变化相关以启动窦的形成， 以及细胞间粘附和细胞间粘附的特定变化，我们假设这将 稳定并加强最终结构。层粘连蛋白亚型在指导滋养细胞行为中的作用， 将检查细胞骨架和粘附变化在维持其结构中的重要性。这些 实验将阐明调节滋养层细胞行为和分化的机制， 对胚胎植入有更深入的了解。

PROVIDED. Implantation of the embryo into the uterus and subsequent formation of the placenta are unique and critical features of mammalian development. They are mediated by the trophoblast cells which arise from the epithelial trophectoderm cells of the blastocyst. At the time of implantation they transform into invasive cells that displace and phagocytose the uterine epithelial cells in order to penetrate the uterine stroma and make vascular connections with the matemal blood supply. The cellular behaviors associated with the transformation of the epithelial trophectoderm into a motile trophoblast and subsequently to an endothelial trophoblast giant cell are important for the success of implantation and placentation and ultimately for the development of the embryo itself. However our understanding of the key cellular events involved in these two transitions, and of their regulation, is still quite rudimentary. The central hypothesis being tested in this proposal is that regulated changes inthe motile behavior of trophoblast cells are the basis for their function in implantation and placentation. The proposed experiments focus on two aspects of trophoblast giant cell differentiation: first, the transition of epithelial trophectoderm to motile trophobiast, and second, the transition from motile trophoblast to trophoblast giant cell. The onset of motility in the trophectoderm is regulated by the availability of amino acids, in particular leucine and arginine. The functions of the signalling mechanisms activated by these amino acids in regulating the onset of _rotrusive activity of the trophectoderm will be characterized, especially with respect to the roles of nitric _xide and polyamine synthesis. After implantation, trophoblast cells form the intricate anastomotic network of _lood sinuses of the yolk sac placenta as they undergo terminal differentiation to trophoblast giant cells. This _rocess is associated with further changes in motility and cell shape to initiate the formation of the sinuses, as well as specific changes in cytoskeletat organization and cell-cell adhesion, which we hypothesize will stabilize and reinforce the final structure. The roles of laminin isoforms in directing trophoblast behavior, and the importance of cytoskeletal and adhesive changes in maintaining their structure will be examined. These experiments will clarify the mechanisms regulating trophoblast cell behavior and differentiation, and will provide a deeper overall understanding of embryo implantation.