Normal human fetal growth and development depend upon a highly regulated cascade of developmental events leading to hemochorial placentation, establishment of uteroplacental contacts and, in late gestation, preparation for perinatal transition. In placenta, the processes of trophoblast proliferation, migration, differentiation, cell fusion and apoptosis are collapsed into the period of gestation. This provides a unique model to study the genes which direct these key maturational events. In addition, abnormal trophoblast differentiation and invasiveness are associated with several common disorders of pregnancy such as intrauterine growth restriction (IUGR), preeclampsia, early pregnancy loss and placenta accreta. We have shown that certain features of human trophoblast differentiation in vivo can be recapitulated in vitro. In preliminary studies we also have uncovered regulatory roles during human trophoblast development for two endogenous polypeptides, the hormone calcitonin and the hormonally-stimulated cytokine interleukin-11 (IL-11). We hypothesize that these factors represent novel physiological modulators of trophoblast differentiation through their actions on trophoblast regulatory genes. We will investigate the effects of these specific factors and their signaling pathways upon trophoblast proliferation, migration and invasiveness, endocrine function and syncytium formation. We also will examine cell cycle regulators involved with differentiation of myoblasts (which also undergo syncytium formation) and hepatocyte cell cycle regulators identified in Subproject I for their effects on trophoblast differentiation. We will identify cell cycle inhibitors and other novel genes differentially regulated during hormone- stimulated trophoblast differentiation. We will isolate and clone these differentially regulated cDNAs and investigate their temporal and cell specific expression during placental development and in pathological samples. The identification of the role of these mechanisms of placental differentiation will provide new pathophysiologic insights into development.
