Fine-Tuned and Cell-Cycle-Restricted Expression of Fusogenic Protein Syncytin-2 Maintains Functional Placental Syncytia

Abstract

Summary: Many types of multinucleated cells (syncytia) generated by cell-cell fusion are post-mitotic, but it remains unclear how this state is maintained and why. Here, we utilized the fluorescent ubiquitination-based cell-cycle indicator (Fucci) reporter system to show that human placental trophoblast cells were all in the G0 phase before they fuse. Expression of the fusogenic protein (fusogen) Syncytin-2 was confined to G0 cells. Overexpression of Syncytin-2 in cycling cells overrode the cell-cycle restriction and enabled fusion of cells in the S/G2/M phases but resulted in the unstable syncytia retaining mitotic features. The Syncytin-2-induced syncytia were functionally compromised with respect to pathogen defense and hormone secretion. We found that, during trophoblast fusion, the cell-cycle inhibitor p21 interacted with the GCM1 transcription factor, and this complex bound to the promoter of Syncytin-2 and promoted its transcription. These findings demonstrate that G0-restricted Syncytin-2 expression is a prerequisite for development of functional post-mitotic syncytia. : Lu et al. demonstrate that G0-phase-restricted fusogenic protein Syncytin-2 is essential for maintenance of functional human placental syncytia. Overexpression of Syncytin-2 overrides cell-cycle restriction and results in functionally compromised syncytia carrying mitotic features. p21 coordinates with transcription factor GCM1 to regulate Syncytin-2 transcription to guarantee appropriate human trophoblast fusion. Keywords: cell fusion, fusogenic protein, syncytin, cell cycle, p21, placenta