Cadherin-11 modulates the terminal differentiation and fusion of human trophoblastic cells in vitro.

E-cadherin and cadherin-11 are two members of the cadherin gene family of cell adhesion molecules that are differentially expressed during the aggregation, differentiation, and fusion of trophoblasts isolated from the human term placenta. E-cadherin expression is highest in cytotrophoblasts and decreases as these mononucleate cells undergo terminal differentiation and fusion. In contrast, cadherin-11 expression increases during the formation of multinucleated syncytium in these primary cultures. To define the role(s) of cadherin-11 in this developmental process, we examined the effects of ectopic cadherin-11 expression on the differentiation and fusion of JEG-3 choriocarcinoma cells, a mononucleate trophoblastic cell line. Cadherin-11 expression, but not the ectopic expression of the related cadherin subtype, cadherin-6, resulted in the formation of multinucleated syncytium in the transfected JEG-3 cell cultures. Multinucleated syncytium formation in the JEG-3 cells transfected with cadherin-11 was associated with a reduction in E-cadherin, alpha-, beta-, gamma-catenin, and p120(ctn) expression. Cadherin-11 also reduced cell proliferation and increased the levels of the mRNA transcript encoding the beta subunit of human chorionic gonadotropin, a biochemical marker of trophoblast differentiation, in these cultures. Furthermore, primary cytotrophoblasts cultured in the presence of antisense oligonucleotides specific for cadherin-11 maintained E-cadherin expression and did not undergo terminal differentiation and fusion with time in culture. Collectively, these observations demonstrate that cadherin-11 contributes to the morphological and functional differentiation of cultured mononucleate trophoblastic cells in a highly specific manner.