Embryonic and uterine signals in mammalian embryo development and implantation. 1) The role of histamine in embryo development and implantation. Because of vasoactive nature, histamine has been considered to be an important mediator in the initiation of blastocyst implantation process. However, neither the sites of formation of histamine nor its mode of action in implantation has not been defined. The dogma was that histamine required for implantation is derived from the resident mast cells in the uterus. However, we have demonstrated for the time that uterine epithelial cells are the major source of histamine, which peaks on day 4 of pregnancy (the day of implantation) in the mouse. In searching for its target and site of action, we found that preimplantation blastocyst, which express histamine type-2 receptor, is the target for histamine action. Using multiple approaches, we also demonstrated that uterine-derived histamine interacts with embryonic histamine type-2 receptors in a paracrine fashion to initiate the process of implantation. 2) Signaling molecules involve in the initiation of progesterone-dependent implantation in hamsters. The implantation process depends on the coordinated interactions between the blastocyst and endometrium being executed by local exchange of signals involving growth factors and cytokines. Much of what is known about these embryo-uterine signaling systems have been derived from studies in the mouse and rat, in which ovarian progesterone and estrogen are absolute requirements for implantation. However, it is not yet clearly established whether any of these signaling systems is operative during implantation in other species like hamsters, guinea pigs, rabbits and monkeys in which embryo implantation can occur in the absence of ovaries if only progesterone is given exogenously. Although progesterone is an absolute requirement for monkey and human implantation, it has become controversial whether ovarian estrogen is also a requirement. It is also unknown whether delayed implantation occurs in humans. Thus, the question remains answered regarding the mechanism by which progesterone alone regulates uterine and embryonic functions for implantation in many species. It is also not clear whether species-specific differential steroid hormonal requirements are reflected in differential regulation of local implantation-specific factors. In an initial study we observed that heparin-binding EGF-like growth factor HB-EGF) is expressed in the uterus in a spatiotemporal implantation specific manner in hamsters. Since implantation in hamsters occurs presumably in the absence of circulating estrogen, we sought to examine whether uterine expression of this gene is regulated by progesterone alone. To our surprise, we noted that uterine expression of HB-EGF is regulated by estradiol-17รข but not by progesterone, in ovariectomized hamsters. These results suggest the existence of an alternate source of estrogen beside the ovary in hamsters. It is possible that preimplantation embryos of the hamster produce estrogen that can act locally to influence uterine gene expression during implantation. 3. Mechanisms of protection of the implanting embryo from maternal dangers: influence of implanting blastocyst in creation of a uterine decidual barrier to escape from maternal dangers The processes of implantation and the formation of primary and secondary decidual zones (PDZ and SDZ) by uterine stromal cells encircling the implanted semi-allogenic blastocyst are notable among many crucial events that must occur correctly in order to continue normal pregnancy. Major pregnancy loss in mammals including humans occurs during early implantation, and one of the reasons for this is abnormal maternal and fetal interaction. This problem entails substantial maternal and embryonic morbidity and motility. Thus, it remains to be determined the mechanisms by which semi-allogenic embryo evades maternal attack during normal p