TROPHOBLAST DIFFERENTIATION

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The chorioallantoic placenta plays an essential role in the development of the fetus. Trophoblast cells, the parenchymal cells of the placenta, are involved in regulating the transport of nutrients and wastes between maternal and fetal compartments, producing hormones that control the growth and metabolism of maternal and fetal cells, and in preventing immunologic rejection of the genetically disparate embryo. Cellular and biochemical mechanisms controlling trophoblast cell growth and differentiation are yet to be elucidated. Consequences of disrupted placental development may be conspicuous resulting in the cessation of pregnancy or more subtle resulting in impaired fetal growth and maturation. Difficulties accompanying fetal development are associated with increased health care needs postnatally. The purpose of this proposal is to identify and characterize cellular and molecular mechanisms involved in directing trophoblast cell differentiation and in maintaining the differentiated trophoblast phenotype. The analysis will be largely focused on the endocrine differentiation of trophoblast cells. We hypothesize that trophoblast cell differentiation is dependent upon interactions with mesenchyme of maternal (uterine decidua) and fetal origin. These interactions influence the organization of the placenta and its access to signals emanating from maternal and fetal environments. Studies will utilize the developing rat chorioallantoic placenta and cell lines established from rat placental primordia. The developing rat chorioallantoic placenta is an excellent model system in that its responses to fetal and maternal interactions are readily dissociable. Two major specific aims presented in the form of questions will be addressed in the proposal: 1) What factors are responsible for the functional and morphological phenotypes of the zones of the rat chorioallantoic placenta? and 2) What is the origin of the rat trophoblast cell lines and what do they represent? Molecular and immunologic probes will be utilized to examine the expression of four measures of the differentiated trophoblast phenotype (placental lactogen-II, placental prolactin-like protein-A, P450scc, and alkaline phosphatase).Expression will be monitored biochemically and histologically in experimentally manipulated trophoblast cells. Studies are designed to evaluate roles of the extracellular matrix, maternal and fetal factors, steroid hormones and cyclic AMP in directing trophoblast cell differentiation. Identification of factors responsible for controlling trophoblast cell differentiation will significantly add to our knowledge of a fundamental embryologic process. Furthermore, these studies will permit identification of developmental stages susceptible to pathologic disruption and thus, potential targets for therapeutic intervention.