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

Abstract

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.

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References

  1. 1

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

  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).

  3. 3

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

  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).

  5. 5

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

  6. 6

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

  7. 7

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

  8. 8

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

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  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).

  17. 17

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

  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).

  19. 19

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

  20. 20

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

  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).

  22. 22

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

  23. 23

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

  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).

  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).

  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).

  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).

  28. 28

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

  29. 29

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

  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).

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Acknowledgements

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.

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Correspondence to John M. McCoy.

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Further reading

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.

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