Mechanisms of implantation in the mouse: differentiation and functional importance of trophoblast giant cell behavior.

According to Lewis Wolpert, “It is not birth, marriage or death, but gastrulation which is truly the most important time in your life” (quoted in Slack, 1983). While it is certainly true that gastrulation is a vitally important morphogenetic event, the argument can be made for us, and for all placental mammals, that implantation is an equally important event in our lives. If implantation fails, so does gastrulation and all subsequent developmental events. Unlike most vertebrate embryos, mammalian embryos require an external source of nutrients to grow and develop. The mouse embryo and those of humans and other primates accomplish this by forming contacts with the maternal blood supply, leading to the formation of a hemochorial placenta (Mossman, 1937; Perry, 1981). Two events are critical to the success of placentation: implantation and the formation of vascular connections. Implantation begins with the apposition and attachment of the embryo to the uterine epithelium, followed by displacement of this epithelium and invasion of the underlying stromal compartment. After implantation has begun, an anastomotic network of blood spaces is formed surrounding the embryo that is continuous with maternal capillaries (Cross et al., 1994; Welsh and Enders, 1987). These blood-filled spaces provide nutrients and oxygen to the embryo during the period before the definitive chorioallantoic placenta is formed, allowing the embryo to grow and differentiate. Both implantation and early vasculogenesis are mediated by trophoblast giant cells, which arise from the epithelial trophectoderm layer of the blastocyst. Trophoblast cell differentiation represents the first divergence of embryonic lineage, and comprises many of the cellular processes seen in other developmental events: cell polarization, epithelialization, and epithelial–mesenchymal transition. The process of transformation of trophectoderm into invasive trophoblast, and then into a vascular network, has many aspects in common with other developmental events, and with gastrulation in particular. Understanding implantation is thus important not only from a clinical standpoint, but unraveling the complex mechanisms that establish and regulate the behavior of this unique extra-embryonic lineage will complement and extend our understanding of the cellular processes that shape the embryo proper. Until recently, most of our knowledge of trophoblast giant cell differentiation and function was morphological, and little was known of the underlying molecular or cellular events. The development of in vitro model systems, the Rcho-1 and trophoblast stem (TS) cell lines (Faria and Soares, 1991; Tanaka et al., 1998), and the ability to delete relevant genes in the mouse have facilitated the analysis of the molecular mechanisms regulating trophoblast giant cell differentiation (reviewed in Cross, 2000; Rinkenberger et al., 1997). However, exploration of the temporal and causal relationships between molecular differentiation and functional cell behavior is just beginning. This review will focus on the cellular aspects of trophoblast giant cell differentiation and their correlation with known molecular aspects of differentiation, as a means of promoting the synthesis of these two approaches.