Trophoblast fusion: Fusogenic proteins, syncytins and ADAMs, and other prerequisites for syncytial fusion

Trophoblast fusion in the placenta is an event of major importance for the preservation of a healthy pregnancy. This process takes place throughout pregnancy and is crucial for the maintenance of the syncytiotrophoblast layer, the direct border between maternal blood and fetal tissues. Different regulatory proteins have been reported that are involved in trophoblast fusion. Syncytin-1 is a candidate regulator of fusion together with its receptors ASCT2 (RDR) and ASCT1. Little is known about the receptor properties and the interactions between receptor and ligand. Syncytin-2 or HERV-FRD is another strong candidate also of retroviral origin; while its actual function still remains to be explored. ADAM12 has been proposed to be a candidate regulator of trophoblast fusion since it is known to be involved in myoblast fusion, a process with a variety of similarities to trophoblast fusion. Beside these regulatory proteins, there is the necessity of a flip of phosphatidylserine from the inner to the outer leaflet of the plasma membranes of the fusing cells. Moreover, appropriate events of the early and still reversible stages of the apoptosis cascade are indispensable for trophoblast fusion. In this review, we present some details on the above events and proteins with their most important properties that could explain their roles in trophoblast fusion.