Involvement of syncytin glycoprotein in human trophoblast cell differentiation and endocrine activity

Objectives: During human pregnancy, the multinuclear syncytiotrophoblast layer performs the main physiological functions of the placenta including hormone production (e.g., beta-HCG). The process of syncytium formation requires essentially what might be designated as the „syncytin system“, a regulatory unit within the human placenta consisting of the fusogenic glycoprotein syncytin-1, its receptor, and, eventually, an intracellular signal molecule, the transcription factor Glial Cells Missing a (GCMa).

Methods: We here tested the effects of protein kinase A (PKA) stimuli and cAMP analogues known to promote, e.g., trophoblastic cell differentiation and endocrine function. Additionally, we focused on the effects of hypoxia and other apoptotic challenges on GCMa and syncytin levels, cellular differentiation and, eventually, hormone production in trophoblastic cells or in syncytin-transfected cells.

Results: Here, we demonstrate that the protein kinase A (PKA) pathway acts upstream of GCMa and syncytin. After transient transfection of trophoblastic cells with PKA, both GCMa and syncytin transcripts were upregulated. This increase was accompanied by further cellular differentiation and pronounced beta-HCG production. Moreover, syncytin-transfected cells were four times more resistant against apoptotic challenges than mock-treated controls.

Conclusion: We propose that GCMa-driven syncytin expression is the key mechanism for syncytiotrophoblast formation along with beta-HCG production. We also found that gene repressive effects of oxygen deficiency were compensated by the induction of the PKA pathway. Conclusively, our data provide evidence that, as a major effect, syncytin serves anti-apoptotic functions and promotes trophoblast cell differentiation and endocrine activity.