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Molecular and Cellular Biology, May 2003, p. 3566-3574, Vol. 23, No. 10
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.10.3566-3574.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Direct Involvement of HERV-W Env Glycoprotein in Human Trophoblast Cell Fusion and Differentiation

Unité INSERM 427, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 75006 Paris,¹ UMR 2142 CNRS-bioMérieux, IFR-128 Biosciences Lyon-Gerland, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07,² Laboratoire de Génétique Moléculaire, Faculté de Pharmacie René Descartes, Paris V, 75270 Paris,³ Institut d'HistoCytopathologie, 33175 Le Bouscat, France⁴

Received 4 October 2002/ Returned for modification 20 December 2002/ Accepted 13 February 2003

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.

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