3.1.1. Blastocyst Transport and Orientation

After fertilization, the embryo encased in a non-anchored glycocalix, the so-called zona pellucida, which prevents ectopic implantation, descends the Fallopian tube and reaches the uterine cavity, while undergoing profound morphological changes ending in the formation of the blastocyst [205,206]. For successful implantation into the maternal tissues, a correct orientation of the blastocyst towards the uterine wall is needed. In most eutherian mammals, at the time of first contact of the blastocyst with the endometrial epithelium, the ICM of the various embryos has an almost constantly specific orientation toward the uterus. In humans, the ICM faces the uterine wall. This positioning of the ICM usually correlates with the site of trophectoderm attachment to the endometrium, as well as with subsequent development of the fetal membranes and placental structures [207,208]. In rodents, implantation occurs in anti-mesometrial position with the ICM facing the mesometrium [209]. Why, within most species, the ICM of the blastocyst, or the placenta, should be positioned consistently in the same way with respect to the uterine wall is not completely understood. Moreover, how the blastocyst becomes correctly oriented [210,211] or what directs the process has not been well clarified, for even the most commonly-studied mammals. However, it has been postulated that orientation depends on signals from the endometrium rather than from the embryo, since embryo-mimicking structures (beads, bubbles or cells) end up in the position that the embryo would occupy [212–215]. For example, in mice endometrial expression of the transcriptional regulator Rbpj is required to instruct embryo orientation, and its conditional deletion determines loss of ventral-dorsal orientation [216]. A role for endometrial glands in embryo orientation has been also proposed. Indeed, recent data indicate that in mice endometrial gland development is confined to the anti-mesometrial side of the uterus [217]. In consideration of the above discussed essential role of uterine glands in implantation, it can be speculated that glands may drive the anti-mesometrial orientation of the implanting mouse embryo, possibly through the expression of specific factors. In this respect, it has been shown that Wnt signaling activity in the mouse uterus is limited to the anti-mesometrial region and a role for Wnt proteins in anti-mesometrial localization of the implanting embryo has been proposed [217].
