Factors Involved in Regulating Trophoblast Fusion: Potential Role in the Development of Preeclampsia

Schematic representation of factors involved in trophoblast fusion (with permission from Gauster et al. [7]). Growth factors, cytokines and hormones from the fetal and/or maternal environment bind to their cognate receptors on the plasma membrane of villous cytotrophoblasts. This may lead to activation of cascades such as those involving protein kinase A (PKA) or MAP kinases ERK1/2 and p38 resulting in increased protein expression of e.g. the transcription factor GCMa, which in turn drives transcription of fusogenic factors. Such factors are mostly structural and membrane proteins that were suggested to promote trophoblast fusion. They include syncytin 1 and its receptor ASCT2 (1), CD98 and its receptor galectin 3 (2) and connexin 43 (3). Other pathways may be activated, too. One recently described pathway is the cytokine-induced conversion of pro-caspase 8 into active caspase 8. Once activated, caspase 8 may act to mediate inactivation of “flippases” and/or activation of “floppases” to trigger the externalization of phosphatidylserine from the inner to the outer leaflet of the plasma membrane (PS flip) (4). Furthermore, caspase 8 may trigger the reorganization of the sub-membranous cytoskeleton by degradation of structural proteins such as α-fodrin (5).