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 in the 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 trophoblast, 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 signaling mechanisms activated by these amino acids in regulating the onset of protrusive activity of the trophectoderm will be characterized, especially with respect to the roles of nitric oxide and polyamine synthesis. After implantation, trophoblast cells form the intricate anastomotic network of blood sinuses of the yolk sac placenta as they undergo terminal differentiation to trophoblast giant cells. This process 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.
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