Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis


Many mammalian viruses have acquired genes from their hosts during their evolution1. The rationale for these acquisitions is usually quite clear: the captured genes are subverted to provide a selective advantage to the virus. Here we describe the opposite situation, where a viral gene has been sequestered to serve an important function in the physiology of a mammalian host. This gene, encoding a protein that we have called syncytin, is the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W2. We find that the major sites of syncytin expression are placental syncytiotrophoblasts, multinucleated cells that originate from fetal trophoblasts. We show that expression of recombinant syncytin in a wide variety of cell types induces the formation of giant syncytia, and that fusion of a human trophoblastic cell line expressing endogenous syncytin can be inhibited by an anti-syncytin antiserum. Our data indicate that syncytin may mediate placental cytotrophoblast fusion in vivo, and thus may be important in human placental morphogenesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Primary sequence and hydrophobicity plot of human syncytin.
Figure 2: Syncytin gene distribution and expression. a, Northern blots showing syncytin expression in human tissues.
Figure 3: In situ hybridizations and syncytin-mediated COS cell fusion.
Figure 4: Fusion of BeWo choriocarcinoma cells to GFP-labelled COS cells.


  1. 1

    Ploegh, H. L. Viral strategies of immune evasion. Science 280, 248–253 (1998).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Blond, J.-L. et al. Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J. Virol. 73, 1175–1185 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Jacobs, K. A. et al. A genetic selection for isolating cDNAs encoding secreted proteins. Gene 198, 289– 296 (1997).

    CAS  Article  Google Scholar 

  4. 4

    Cross, J. C., Werb, Z. & Fisher, S. J. Implantation and the placenta: key pieces of the development puzzle. Science 266, 1508– 1518 (1996).

    ADS  Article  Google Scholar 

  5. 5

    Lala, P. K. & Hamilton, G. S. Growth factors, proteases and protease inhibitors in the maternal fetal dialog. Placenta 17, 545–555 (1996).

    CAS  Article  Google Scholar 

  6. 6

    Munn, D. H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Yamada, S. & Ohnishi, S. Vesicular stomatitis virus binds and fuses with phospholipid domain in target cell membranes. Biochemistry 25, 3703–3708 ( 1986).

    CAS  Article  Google Scholar 

  8. 8

    Pattillo, R. A., Gey, G. O., Delfs, E. & Mattingly, R. F. Human hormone production in vitro. Science 159, 1467–1469 (1968).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Lyden, T. W., Ng, A-K. & Rote, N. S. Modulation of phosphatidylserine epitope expression by BeWo cells during forskoloin treatment. Placenta 14, 177– 186 (1993).

    CAS  Article  Google Scholar 

  10. 10

    Kohler, P. O. & Bridson, W. E. Isolation of hormone-producing clonal lines of human choriocarcinoma. J. Clin. Endocrinol. Metab. 32, 683–687 ( 1971).

    CAS  Article  Google Scholar 

  11. 11

    Larsson, E. et al. Expression of an endogenous retrovirus, HERV-R, in human tissues. J. Cancer Res. Clin. Oncol. 119 (Suppl. 1), 6 (1993).

    Google Scholar 

  12. 12

    Boyd, M. T., Bax, C. M., Bax, B. E., Bloxam, D. L. & Weiss, R. A. The human endogenous retrovirus ERV-3 is upregulated in differentiating placental trophoblast cells. Virology 196, 905–909 (1993).

    CAS  Article  Google Scholar 

  13. 13

    Venables, P. J., Brookes, S. M., Griffiths, D., Weiss, R. A. & Boyd, M. T. Abundance of an endogenous retroviral envelope protein in placental trophoblasts suggests a biological function. Virology 211, 589–592 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Limjoco, T. I., Dickie, P., Ikeda, H. & Silver, J. Transgenic Fv-4 mice resistant to Friend virus. J. Virol. 67, 4163–4168 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Best, S., Le Tissier, P., Towers, G. & Stoye, J. P. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 382, 826–829 (1996).

    ADS  CAS  Article  Google Scholar 

  16. 16

    Kalter, S. S. et al. A comparative study on the presence of C-type viral particles in placentas from primates and other animals. Bibl. Haematol. 40, 391–401 (1975).

    Google Scholar 

  17. 17

    Harris, J. R. The evolution of placental mammals. FEBS Lett. 295, 3–4 (1991).

    CAS  Article  Google Scholar 

  18. 18

    Pijnenborg, R., Robertson, W. B., Brosens, I. & Dixon, G. Trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta 2, 71–92 (1981).

    CAS  Article  Google Scholar 

  19. 19

    Fox, H. in Pathology of the Placenta Chapter 6 (ed. Fox, H.) 151– 175 (W. B. Saunders, Philadelphia, 1997).

    Google Scholar 

  20. 20

    Baergen, R. N. Gestational choriocarcinoma. Gen. Diagn. Pathol. 143 , 127–141 (1997).

    CAS  PubMed  Google Scholar 

  21. 21

    Cianciolo, G. J., Copeland, T. D., Oroszlan, S. & Snyderman, R. Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Science 230, 453–455 (1985).

    ADS  CAS  Article  Google Scholar 

  22. 22

    Kovats, S. et al. A class I antigen, HLA-G, expressed in human trophoblasts. Science 248, 220–223 ( 1990).

    ADS  CAS  Article  Google Scholar 

  23. 23

    Hunt, J. S. Immunobiology of pregnancy. Curr. Opin. Immunol. 4, 591–596 (1992).

    CAS  Article  Google Scholar 

  24. 24

    Cohen, M., Powers, M., O'Connell, C. & Kato, N. The nucleotide sequence of the env gene from the human provirus ERV3 and isolation and characterization of an ERV3-specific cDNA. Virology 147, 449–458 (1985).

    CAS  Article  Google Scholar 

  25. 25

    Larsson, E., Andersson, A. C. & Nilsson, B. O. Expression of an endogenous retrovirus (ERV3 HERV-R) in human reproductive and embryonic tissues—evidence for a function for envelope gene products. Ups. J. Med. Sci. 99, 113–120 (1994).

    CAS  Article  Google Scholar 

  26. 26

    Lin, L., Xu, B. & Rote, N. S. Expression of endogenous retrovirus ERV-3 induces differentiation in BeWo, a choriocarcinoma model of human placental trophoblast. Placenta 20, 109–118 ( 1999).

    CAS  Article  Google Scholar 

  27. 27

    Kaufman, R. J., Davies, M. V., Wasley, L. C. & Michnick, D. Improved vectors for stable expression of foreign genes in mammalian cells by use of the untranslated leader sequence from EMC virus. Nucleic Acids Res. 19, 4485–4490 (1991).

    CAS  Article  Google Scholar 

  28. 28

    Sassoon, D. & Rosenthal, N. Detection of messenger RNA by in situ hybridization. Methods Enzymol. 225, 384–404 (1993).

    CAS  Article  Google Scholar 

  29. 29

    Fischer, D., Weisenberger, D. & Scheer, U. Assigning functions to nucleolar structures. Chromosoma 101, 133–140 (1991).

    CAS  Article  Google Scholar 

  30. 30

    Gately, M. K., Chizzonite, R. & Presky, D. H. in Current Protocols in Immunology 6. 16 (eds Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M. & Strober, W.) (Wiley, New York, 1996).

    Google Scholar 

Download references


We thank the Genetics Institute signal sequence trap team for the initial cloning of syncytin; J. Wooters for help in liposome preparations; B. Gimlich, I. Moutsatsos and the Genetics Institute Developmental Biology group for microscopy assistance; the Genetics Institute DNA synthesis group for oligonucleotides; and M. Davies, R. Pijnenborg and K. Turner for critical review of this manuscript.

Author information



Corresponding author

Correspondence to John M. McCoy.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mi, S., Lee, X., Li, X. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis . Nature 403, 785–789 (2000).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.