Role and regulation of Ca2+ flux during the cell-cell fusion occurring in the human placenta

The cell-cell fusion processes are complex biological phenomena. A limited number of human cell types can fuse to form a multinucleated syncytium. In the differentiation of human placenta, mononuclear cytotrophoblasts aggregate and fuse to form an endocri nologically active, non-proliferative, multinucleated syncytiotrophoblast. The molecular events underlying this process remain poorly understood. In the human placenta, the cellular fusion plays an extremely important role. Indeed, this is the limiting st ep for the placenta formation, indispensable organ for fetal development and growth. This essential process is engaged after activation of the cAMP-PKA signaling pathway by hCG (human chorionic gonadotropin). Common gestational pathologies are associated with a defect of cell-cell fusion and differentiation in the human placenta. These pathologies are named preeclampsia and IUGR (IntraUterine Growth Retardation) and are always associated with premature birth, which is a public health problem in western co untries (severe motor, neuro-sensorial and respiratory deficiencies for pre-birth children and a cost for social protection system far from negligible). In this project we proposed to study some mechanisms involved in trophoblastic cell fusion. Our prelim inary results indicated that calcium is necessary for cell fusion under hCG induction and demonstrate the implication of A kinase anchoring proteins (AKAPs) into this process by cellular delivery of PKA anchoring disruptor peptides. We propose to determin e by different biochemical approaches the origin of calcium flux involved in cell fusion under hCG stimulation. In another hand, we want to elucidate the role of AKAPs into the regulation of calcium flux during syncytialisation. Outcomes from this project will allow to understand molecular mechanisms involved in cell fusion but will also provide in a long term new treatments for pathologies of the pregnancy presenting a defect of cell fusion and syncytial formation.