Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation.
We recently demonstrated that the product of the HERV-W env gene, a retroviral envelope protein also dubbed syncytin, is a highly fusogenic membrane glycoprotein inducing the formation of syncytia on interaction with the type D mammalian retrovirus receptor. In addition, the detection of HERV-W Env protein (Env-W) expression in placental tissue sections led us to propose a role for this fusogenic glycoprotein in placenta formation. To evaluate this hypothesis, we analyzed the involvement of Env-W in the differentiation of primary cultures of human villous cytotrophoblasts that spontaneously differentiate by cell fusion into syncytiotrophoblasts in vitro. First, we observed that HERV-W env mRNA and glycoprotein expression are colinear with primary cytotrophoblast differentiation and with expression of human chorionic gonadotropin (hCG), a marker of syncytiotrophoblast formation. Second, we observed that in vitro stimulation of trophoblast cell fusion and differentiation by cyclic AMP is also associated with a concomitant increase in HERV-W env and hCG mRNA and protein expression. Finally, by using specific antisense oligonucleotides, we demonstrated that inhibition of Env-W protein expression leads to a decrease of trophoblast fusion and differentiation, with the secretion of hCG in culture medium of antisense oligonucleotide-treated cells being decreased by fivefold. Taken together, these results strongly support a direct role for Env-W in human trophoblast cell fusion and differentiation.
Unité INSERM 427, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 75006 Paris, France.
Jean-Louis
JL
Frendo
Delphine
D
Olivier
Valérie
V
Cheynet
Jean-Luc
JL
Blond
Olivier
O
Bouton
Michel
M
Vidaud
Michèle
M
Rabreau
Danièle
D
Evain-Brion
François
F
Mallet
D002454:Cell Differentiation; D002459:Cell Fusion; D020077:Endogenous Retroviruses / Q000378:metabolism*; D015686:Gene Products, env / Q000235:genetics*; D015726:Giant Cells / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014327:Trophoblasts / Q000378:metabolism*
D015686:Gene Products, env; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012313:RNA