Mammalian embryonic development and growth require implantation into the uterus. In mammals that form a hemochorial placenta (eg, humans, mice), embryonictrophoblast cells enable the embryo to invade through the uterine epithelium and deep into the stroma. The penetrative nature of hemochorial placentation so mimics that seen with highly invasive tumors that the normal trophoblast has been called pseudomalignant. Thus, in normal pregnancies the uterus must act to limit implantation; the uncontrolled invasion of the trophoblast, as in choriocarcinoma, results in one of the most metastatic tumors known. Recent work using both naturally occurring and experimentally generated mouse mutations has shed new light on implantation and its regulation. Present knowledge can be considered from the perspective of the two interacting tissues: the trophoblast and the uterus. The Trophoblast

In mice and humans, trophoblast cells must cross the basement membranes of the uterine epithelium and vasculature to effect successful implantation. It has long been suspected that proteolytic enzymes play a role in this process. For example, the production of the protease urokinase-type plasminogen activator (U-PA) by mouse trophoblast cells temporally coincides with the embryo’s invasive phase and is localized to regions of invasion (Strickland et al., 1976; Sappino et al., 1989). Human trophoblast cells also express U-PA receptor (Mini et al., 1992), which can bind active U-PA and localize proteolysis to the leading edge of migrating cells (Estreicher et al., Roldan et al., 1990). In addition, mouse embryos homozygous for the mutation rY73 have reduced levels of PA and do not implant (Axelrod, 1985).