Citation: Yufei Zhang, Jing Shi, Shuying Liu. Recent advances in the study of active endogenous retrovirus envelope glycoproteins in the mammalian placenta .VIROLOGICA SINICA, 2015, 30(4) : 239-248.

Recent advances in the study of active endogenous retrovirus envelope glycoproteins in the mammalian placenta

  • Corresponding author: Shuying Liu,
  • Yufei Zhang, ORCID: 0000-0002-8025-6705
  • Received Date: 26 June 2015
    Accepted Date: 14 August 2015
    Published Date: 18 August 2015
    Available online: 01 August 2015
  • Endogenous retroviruses (ERVs) are a component of the vertebrate genome and originate from exogenous infections of retroviruses in the germline of the host. ERVs have coevolved with their hosts over millions of years. Envelope glycoproteins of endogenous retroviruses are often expressed in the mammalian placenta, and their potential function has aroused considerable research interest, including the manipulation of maternal physiology to benefit the fetus. In most mammalian species, trophoblast fusion in the placenta is an important event, involving the formation of a multinucleated syncytiotrophoblast layer to fulfill essential fetomaternal exchange functions. The key function in this process derives from the envelope genes of endogenous retroviruses, namely syncytins, which show fusogenic properties and placenta-specific expression. This review discusses the important role of the recognized endogenous retrovirus envelope glycoproteins in the mammalian placenta.

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    1. Adelson DL, Raison JM, Edgar RC. 2009. Characterization and distributionof retrotransposons and simple sequence repeats in thebovine genome. Proc Natl Acad Sci U S A, 106: 12855-12860.
        doi: 10.1073/pnas.0901282106

    2. Allen TE, Sherrill KJ, Crispell SM, Perrott MR, Carlson JO, DeMartini JC. 2002. The jaagsiekte sheep retrovirus envelopegene induces transformation of the avian fibroblast cell line DF-1but does not require a conserved SH2 binding domain. J GenVirol, 83: 2733-2742.

    3. Armezzani A, Arnaud F, Caporale M, di Meo G, Iannuzzi L, MurgiaC, Palmarini M. 2011. The signal peptide of a recently integratedendogenous sheep betaretrovirus envelope plays a major role ineluding gag-mediated late restriction. J Virol, 85: 7118-7128.
        doi: 10.1128/JVI.00407-11

    4. Armezzani A, Varela M, Spencer TE, Palmarini M, Arnaud F. 2014."Menage a Trois": the evolutionary interplay between JSRV, en-JSRVs and domestic sheep. Viruses, 6: 4926-4945.
        doi: 10.3390/v6124926

    5. Arnaud F, Black SG, Murphy L, Griffiths DJ, Neil SJ, Spencer TE, Palmarini M. 2010. Interplay between ovine bone marrow stromalcell antigen 2/tetherin and endogenous retroviruses. J Virol, 84: 4415-4425.
        doi: 10.1128/JVI.00029-10

    6. Arnaud F, Caporale M, Varela M, Biek R, Chessa B, Alberti A, Golder M, Mura M, Zhang YP, Yu L, Pereira F, Demartini JC, Leymaster K, Spencer TE, Palmarini M. 2007. A paradigm forvirus-host coevolution: sequential counter-adaptations betweenendogenous and exogenous retroviruses. PLoS Pathog, 3: e170.
        doi: 10.1371/journal.ppat.0030170

    7. Baba K, Nakaya Y, Shojima T, Muroi Y, Kizaki K, Hashizume K, Imakawa K, Miyazawa T. 2011. Identification of novel endogenousbetaretroviruses which are transcribed in the bovine placenta. J Virol, 85: 1237-1245.
        doi: 10.1128/JVI.01234-10

    8. Benit L, Dessen P, Heidmann T.2001. Identification, phylogeny, and evolution of retroviral elements based on their envelopegenes. J Virol, 75: 11709-11719.
        doi: 10.1128/JVI.75.23.11709-11719.2001

    9. Bierwolf D, Rudolph M, Niezabitowski A, Jorde A, Bender E, Widmaier R, Graffi A. 1975. [C-type-like particles in normalhuman placentas (author's transl)]. Arch Geschwulstforsch, 45:628-633.

    10. Bjerregaard B, Lemmen JG, Petersen MR, Ostrup E, Iversen LH, Almstrup K, Larsson LI, Ziebe S. 2014. Syncytin-1 and its receptoris present in human gametes. J Assist Reprod Genet, 31:533-539.
        doi: 10.1007/s10815-014-0224-1

    11. Bjerregard B, Ziomkiewicz I, Schulz A, Larsson LI. 2014. Syncytin-1 in differentiating human myoblasts: relationship to caveolin-3 and myogenin. Cell Tissue Res, 357: 355-362.
        doi: 10.1007/s00441-014-1930-9

    12. Black SG, Arnaud F, Palmarini M, Spencer TE. 2010. Endogenousretroviruses in trophoblast differentiation and placental development. Am J Reprod Immunol, 64: 255-264.
        doi: 10.1111/j.1600-0897.2010.00860.x

    13. Blond JL, Beseme F, Duret L, Bouton O, Bedin F, Perron H, MandrandB, Mallet F. 1999. Molecular characterization and placentalexpression of HERV-W, a new human endogenous retrovirusfamily. J Virol, 73: 1175-1185.

    14. Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-FernandesS, Mandrand B, Mallet F, Cosset FL. 2000. An envelopeglycoprotein of the human endogenous retrovirus HERV-W isexpressed in the human placenta and fuses cells expressing thetype D mammalian retrovirus receptor. J Virol, 74: 3321-3329.
        doi: 10.1128/JVI.74.7.3321-3329.2000

    15. Boeke JD, Stoye JP. 1997. Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements. In: Retroviruses, Coffin JM, Hughes SH, and Varmus HE (eds). New York: ColdSpring Harbor, pp. 343-436.

    16. Boyd MT, Bax CM, Bax BE, Bloxam DL, Weiss RA. 1993. Thehuman endogenous retrovirus ERV-3 is upregulated in differentiatingplacental trophoblast cells. Virology, 196: 905-909.
        doi: 10.1006/viro.1993.1556

    17. Chuong EB. 2013. Retroviruses facilitate the rapid evolution of themammalian placenta. Bioessays, 35: 853-861.

    18. Cohen M, Powers M, O'Connell C, Kato N. 1985. The nucleotidesequence of the env gene from the human provirus ERV3 andisolation and characterization of an ERV3-specific cDNA. Virology, 147: 449-458.
        doi: 10.1016/0042-6822(85)90147-3

    19. Cornelis G, Heidmann O, Bernard-Stoecklin S, Reynaud K, VeronG, Mulot B, Dupressoir A, Heidmann T. 2012. Ancestral captureof syncytin-Car1, a fusogenic endogenous retroviral envelopegene involved in placentation and conserved in Carnivora. ProcNatl Acad Sci U S A, 109: E432-441.
        doi: 10.1073/pnas.1115346109

    20. Cornelis G, Heidmann O, Degrelle SA, Vernochet C, Lavialle C, Letzelter C, Bernard-Stoecklin S, Hassanin A, Mulot B, GuillomotM, Hue I, Heidmann T, Dupressoir A. 2013. Captured retroviralenvelope syncytin gene associated with the unique placentalstructure of higher ruminants. Proc Natl Acad Sci U S A, 110:E828-837.
        doi: 10.1073/pnas.1215787110

    21. Cornelis G, Vernochet C, Carradec Q, Souquere S, Mulot B, CatzeflisF, Nilsson MA, Menzies BR, Renfree MB, Pierron G, ZellerU, Heidmann O, Dupressoir A, Heidmann T. 2015. Retroviral envelopegene captures and syncytin exaptation for placentation inmarsupials. Proc Natl Acad Sci U S A, 112: E487-496.
        doi: 10.1073/pnas.1417000112

    22. Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, LiuSL, Miller AD, Lerman MI. 2003. Hyaluronidase 2 negativelyregulates RON receptor tyrosine kinase and mediates transformationof epithelial cells by jaagsiekte sheep retrovirus. ProcNatl Acad Sci U S A, 100: 4580-4585.
        doi: 10.1073/pnas.0837136100

    23. de Parseval N, Lazar V, Casella JF, Benit L, Heidmann T. 2003. Survey of human genes of retroviral origin: identification andtranscriptome of the genes with coding capacity for complete envelopeproteins. J Virol, 77: 10414-10422.
        doi: 10.1128/JVI.77.19.10414-10422.2003

    24. DeHaven JE, Schwartz DA, Dahm MW, Hazard ES, 3rd, TrifilettiR, Lacy ER, Norris JS. 1998. Novel retroviral sequences are expressedin the epididymis and uterus of Syrian hamsters. J GenVirol, 79: 2687-2694.

    25. Dolei A, Uleri E, Ibba G, Caocci M, Piu C, Serra C. 2015. Thealiens inside human DNA: HERV-W/MSRV/syncytin-1 endogenousretroviruses and neurodegeneration. J Infect Dev Ctries, 9: 577-587.
        doi: 10.3855/jidc.6916

    26. Dunlap KA, Palmarini M, Adelson DL, Spencer TE. 2005. Sheependogenous betaretroviruses (enJSRVs) and the hyaluronidase 2(HYAL2) receptor in the ovine uterus and conceptus. Biol Reprod, 73: 271-279.
        doi: 10.1095/biolreprod.105.039776

    27. Dunlap KA, Palmarini M, Varela M, Burghardt RC, Hayashi K, Farmer JL, Spencer TE. 2006. Endogenous retroviruses regulateperiimplantation placental growth and differentiation. Proc NatlAcad Sci U S A, 103: 14390-14395.
        doi: 10.1073/pnas.0603836103

    28. Dupressoir A, Marceau G, Vernochet C, Benit L, KanellopoulosC, Sapin V, Heidmann T. 2005. Syncytin-A and syncytin-B, twofusogenic placenta-specific murine envelope genes of retroviralorigin conserved in Muridae. Proc Natl Acad Sci U S A, 102:725-730.
        doi: 10.1073/pnas.0406509102

    29. Dupressoir A, Vernochet C, Bawa O, Harper F, Pierron G, OpolonP, Heidmann T. 2009. Syncytin-A knockout mice demonstratethe critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene. Proc Natl Acad Sci U S A, 106:12127-12132.
        doi: 10.1073/pnas.0902925106

    30. Dupressoir A, Vernochet C, Harper F, Guegan J, Dessen P, PierronG, Heidmann T. 2011. A pair of co-opted retroviral envelope syncytingenes is required for formation of the two-layered murineplacental syncytiotrophoblast. Proc Natl Acad Sci U S A, 108:E1164-1173.
        doi: 10.1073/pnas.1112304108

    31. Esnault C, Priet S, Ribet D, Vernochet C, Bruls T, Lavialle C, WeissenbachHeidmann T. 2008. A placenta-specific receptor forthe fusogenic, endogenous retrovirus-derived, human syncytin-2. Proc Natl Acad Sci U S A, 105: 17532-17537.
        doi: 10.1073/pnas.0807413105

    32. Frendo JL, Olivier D, Cheynet V, Blond JL, Bouton O, Vidaud M, Rabreau M, Evain-Brion D, Mallet F. 2003. Direct involvementof HERV-W Env glycoprotein in human trophoblast cell fusionand differentiation. Mol Cell Biol, 23: 3566-3574.
        doi: 10.1128/MCB.23.10.3566-3574.2003

    33. Gifford R, Tristem M. 2003. The evolution, distribution and diversityof endogenous retroviruses. Virus Genes, 26: 291-315.
        doi: 10.1023/A:1024455415443

    34. Goff SP. 2001. Intracellular trafficking of retroviral genomes duringthe early phase of infection: viral exploitation of cellular pathways. J Gene Med, 3: 517-528.
        doi: 10.1002/(ISSN)1521-2254

    35. Gong R, Huang L, Shi J, Luo K, Qiu G, Feng H, Tien P, Xiao G.2007. Syncytin-A mediates the formation of syncytiotrophoblastinvolved in mouse placental development. Cell Physiol Biochem, 20: 517-526.

    36. Guillomot M. 1995. Cellular interactions during implantation in domesticruminants. J Reprod Fertil Suppl, 49: 39-51.

    37. Haig D. 2012. Retroviruses and the placenta. Curr Biol, 22: R609-613.
        doi: 10.1016/j.cub.2012.06.002

    38. Haig D. 2013. Genomic vagabonds: endogenous retroviruses andplacental evolution. Bioessays, 35: 845-846.

    39. Harris JR. 1991. The evolution of placental mammals. FEBS Lett, 295: 3-4.
        doi: 10.1016/0014-5793(91)81370-N

    40. Harris JR. 1998. Placental endogenous retrovirus (ERV): structural, functional, and evolutionary significance. Bioessays, 20:307-316.
        doi: 10.1002/(SICI)1521-1878(199804)20:4<>1.0.CO;2-X

    41. Heidmann O, Vernochet C, Dupressoir A, Heidmann T. 2009. Identificationof an endogenous retroviral envelope gene with fusogenicactivity and placenta-specific expression in the rabbit:a new "syncytin" in a third order of mammals. Retrovirology, 6: 107.
        doi: 10.1186/1742-4690-6-107

    42. Henke C, Ruebner M, Faschingbauer F, Stolt CC, Schaefer N, LangN, Beckmann MW, Strissel PL, Strick R. 2013. Regulation ofmurine placentogenesis by the retroviral genes Syncytin-A, Syncytin-B and Peg10. Differentiation, 85: 150-160.
        doi: 10.1016/j.diff.2013.02.002

    43. Henzy JE, Coffin JM. 2013. Betaretroviral envelope subunits arenoncovalently associated and restricted to the mammalian class. J Virol, 87: 1937-1946.
        doi: 10.1128/JVI.01442-12

    44. Henzy JE, Johnson WE. 2013. Pushing the endogenous envelope. Philos Trans R Soc Lond B Biol Sci, 368: 20120506.
        doi: 10.1098/rstb.2012.0506

    45. Herniou E, Martin J, Miller K, Cook J, Wilkinson M, Tristem M.1998. Retroviral diversity and distribution in vertebrates. J Virol, 72: 5955-5966.

    46. Hofacre A, Fan H. 2010. Jaagsiekte sheep retrovirus biology andoncogenesis. Viruses, 2: 2618-2648.
        doi: 10.3390/v2122618

    47. Hosaka M, Nagahama M, Kim WS, Watanabe T, Hatsuzawa K, IkemizuJ, Murakami K, Nakayama K. 1991. Arg-X-Lys/Arg-Argmotif as a signal for precursor cleavage catalyzed by furin withinthe constitutive secretory pathway. J Biol Chem, 266: 12127-12130.

    48. Huang Q, Chen H, Li J, Oliver M, Ma X, Byck D, Gao Y, Jiang SW.2014a. Epigenetic and non-epigenetic regulation of syncytin-1expression in human placenta and cancer tissues. Cell Signal, 26:648-656.
        doi: 10.1016/j.cellsig.2013.11.002

    49. Huang Q, Chen H, Wang F, Brost BC, Li J, Gao Y, Li Z, Gao Y, Jiang SW. 2014b. Reduced syncytin-1 expression in choriocarcinomaBeWo cells activates the calpain1-AIF-mediated apoptosis, implication for preeclampsia. Cell Mol Life Sci, 71: 3151-3164.
        doi: 10.1007/s00018-013-1533-8

    50. Hull S, Lim J, Hamil A, Nitta T, Fan H. 2012. Analysis of jaagsiektesheep retrovirus (JSRV) envelope protein domains in transformation. Virus Genes, 45: 508-517.
        doi: 10.1007/s11262-012-0793-y

    51. Imamura M, Phillips PE, Mellors RC. 1976. The occurrence andfrequency of type C virus-like particles in placentas from patientswith systemic lupus erythematosus and from normal subjects. Am J Pathol, 83: 383-394.

    52. Johnson PM, Lyden TW, Mwenda JM. 1990. Endogenous retroviralexpression in the human placenta. Am J Reprod Immunol, 23:115-120.
        doi: 10.1111/aji.1990.23.issue-4

    53. Kalter SS, Heberling RL, Helmke RJ, Panigel M, Smith GC, KraemerDC, Hellman A, Fowler AK, Strickland JE. 1975. A comparativestudy on the presence of C-type viral particles in placentasfrom primates and other animals. Bibl Haematol: 391-401.

    54. Katzourakis A, Gifford RJ, Tristem M, Gilbert MT, Pybus OG.2009. Macroevolution of complex retroviruses. Science, 325:1512.
        doi: 10.1126/science.1174149

    55. Knerr I, Beinder E, Rascher W. 2002. Syncytin, a novel human endogenousretroviral gene in human placenta: evidence for its dysregulationin preeclampsia and HELLP syndrome. Am J ObstetGynecol, 186: 210-213.
        doi: 10.1067/mob.2002.119636

    56. Koshi K, Suzuki Y, Nakaya Y, Imai K, Hosoe M, Takahashi T, KizakiK, Miyazawa T, Hashizume K. 2012. Bovine trophoblastic celldifferentiation and binucleation involves enhanced endogenousretrovirus element expression. Reprod Biol Endocrinol, 10: 41.
        doi: 10.1186/1477-7827-10-41

    57. Kowalski M, Potz J, Basiripour L, Dorfman T, Goh WC, TerwilligerE, Dayton A, Rosen C, Haseltine W, Sodroski J. 1987. Functionalregions of the envelope glycoprotein of human immunodeficiencyvirus type 1. Science, 237: 1351-1355.
        doi: 10.1126/science.3629244

    58. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, BaldwinJ, Devon K, Dewar K, Doyle M, FitzHugh W, et al. InternationalHuman Genome Sequencing C. 2001. Initial sequencing andanalysis of the human genome. Nature, 409: 860-921.

    59. Leamnson RN, Halpern MS. 1976. Subunit structure of the glycoproteincomplex of avian tumor virus. J Virol, 18: 956-968.

    60. Li K, Zhang S, Kronqvist M, Wallin M, Ekstrom M, Derse D, GaroffH. 2008. Intersubunit disulfide isomerization controls membranefusion of human T-cell leukemia virus Env. J Virol, 82:7135-7143.
        doi: 10.1128/JVI.00448-08

    61. Lin L, Xu B, Rote NS. 1999. Expression of endogenous retrovirusERV-3 induces differentiation in BeWo, a choriocarcinoma modelof human placental trophoblast. Placenta, 20: 109-118.
        doi: 10.1053/plac.1998.0337

    62. Liu SL, Miller AD. 2005. Transformation of madin-darby caninekidney epithelial cells by sheep retrovirus envelope proteins. JVirol, 79: 927-933.
        doi: 10.1128/JVI.79.2.927-933.2005

    63. Lokossou AG, Toudic C, Barbeau B. 2014. Implication of humanendogenous retrovirus envelope proteins in placental functions. Viruses, 6: 4609-4627.
        doi: 10.3390/v6114609

    64. Machnik G, Skudrzyk E, Buldak L, Labuzek K, Ruczynski J, AlenowiczM, Rekowski P, Nowak PJ, Okopien B. 2015. A Novel, Highly Selective RT-QPCR Method for Quantification of MSRVUsing PNA Clamping Syncytin-1 (ERVWE1). Mol Biotechnol.

    65. Maeda N, Palmarini M, Murgia C, Fan H. 2001. Direct transformationof rodent fibroblasts by jaagsiekte sheep retrovirus DNA. Proc Natl Acad Sci U S A, 98: 4449-4454.
        doi: 10.1073/pnas.071547598

    66. Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, HeidmannO, Letzelter C, Richaud A, Ducos B, Heidmann T. 2007. Placentalsyncytins: Genetic disjunction between the fusogenic andimmunosuppressive activity of retroviral envelope proteins. ProcNatl Acad Sci U S A, 104: 20534-20539.
        doi: 10.1073/pnas.0707873105

    67. Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JC, Jr., McCoy JM. 2000.Syncytin is a captive retroviral envelope protein involved in humanplacental morphogenesis. Nature, 403: 785-789.
        doi: 10.1038/35001608

    68. Nakagawa S, Bai H, Sakurai T, Nakaya Y, Konno T, Miyazawa T, Gojobori T, Imakawa K. 2013. Dynamic evolution of endogenousretrovirus-derived genes expressed in bovine conceptuses duringthe period of placentation. Genome Biol Evol, 5: 296-306.
        doi: 10.1093/gbe/evt007

    69. Nakaya Y, Miyazawa T. 2015. The Roles of Syncytin-Like Proteinsin Ruminant Placentation. Viruses, 7: 2928-2942.
        doi: 10.3390/v7062753

    70. Nakaya Y, Koshi K, Nakagawa S, Hashizume K, Miyazawa T.2013. Fematrin-1 is involved in fetomaternal cell-to-cell fusionin Bovinae placenta and has contributed to diversity of ruminantplacentation. J Virol, 87: 10563-10572.
        doi: 10.1128/JVI.01398-13

    71. Omata W, Ackerman WEt, Vandre DD, Robinson JM. 2013. Trophoblastcell fusion and differentiation are mediated by both theprotein kinase C and a pathways. PLoS One, 8: e81003.
        doi: 10.1371/journal.pone.0081003

    72. Palmarini M, Mura M, Spencer TE. 2004. Endogenous betaretrovirusesof sheep: teaching new lessons in retroviral interferenceand adaptation. J Gen Virol, 85: 1-13.
        doi: 10.1099/vir.0.19547-0

    73. Pinter A, Lieman-Hurwitz J, Fleissner E. 1978. The nature of theassociation between the murine leukemia virus envelope proteins. Virology, 91: 345-351.
        doi: 10.1016/0042-6822(78)90382-3

    74. Qi JW, Wu XL, Liu SY, Cao GF. 2012. Expression of endogenousbeta retroviruses and Hyal-2 mRNA in immune organs of fetusesand lambs. Virol Sin, 27: 83-92.
        doi: 10.1007/s12250-012-3222-4

    75. Redelsperger F, Cornelis G, Vernochet C, Tennant BC, Catzeflis F, Mulot B, Heidmann O, Heidmann T, Dupressoir A. 2014. Captureof syncytin-Mar1, a fusogenic endogenous retroviral envelopegene involved in placentation in the Rodentia squirrel-relatedclade. J Virol, 88: 7915-7928.
        doi: 10.1128/JVI.00141-14

    76. Roberts RM, Ealy AD, Alexenko AP, Han CS, Ezashi T. 1999. Trophoblastinterferons. Placenta, 20: 259-264.

    77. Rote NS, Chakrabarti S, Stetzer BP. 2004. The role of human endogenousretroviruses in trophoblast differentiation and placentaldevelopment. Placenta, 25: 673-683.
        doi: 10.1016/j.placenta.2004.02.008

    78. Singh M, Berger B, Kim PS. 1999. LearnCoil-VMF: computationalevidence for coiled-coil-like motifs in many viral membrane-fusionproteins. J Mol Biol, 290: 1031-1041.
        doi: 10.1006/jmbi.1999.2796

    79. Smith CA, Moore HD. 1988. Expression of C-type viral particles atimplantation in the marmoset monkey. Hum Reprod, 3: 395-398.
        doi: 10.1093/oxfordjournals.humrep.a136714

    80. Smith JG, Cunningham JM. 2007. Receptor-induced thiolate couplesEnv activation to retrovirus fusion and infection. PLoS Pathog, 3: e198.
        doi: 10.1371/journal.ppat.0030198

    81. Spencer TE, Johnson GA, Bazer FW, Burghardt RC. 2004. Implantationmechanisms: insights from the sheep. Reproduction, 128:657-668.
        doi: 10.1530/rep.1.00398

    82. Spencer TE, Johnson GA, Bazer FW, Burghardt RC, Palmarini M.2007. Pregnancy recognition and conceptus implantation in domesticruminants: roles of progesterone, interferons and endogenousretroviruses. Reprod Fertil Dev, 19: 65-78.
        doi: 10.1071/RD06102

    83. Spencer TE, Palmarini M. 2012. Application of next generation sequencingin mammalian embryogenomics: lessons learned fromendogenous betaretroviruses of sheep. Anim Reprod Sci, 134:95-103.
        doi: 10.1016/j.anireprosci.2012.08.016

    84. Swanstrom R, Wills JW. 1997. Synthesis, Assembly, and Processingof Viral Proteins. In: Retroviruses, Coffin JM, Hughes SH, and Varmus HE (eds). New York: Cold Spring Harbor, pp263-334.

    85. Tolosa JM, Parsons KS, Hansbro PM, Smith R, Wark PA. 2015. The placental protein syncytin-1 impairs antiviral responses andexaggerates inflammatory responses to influenza. PLoS One, 10:e0118629.
        doi: 10.1371/journal.pone.0118629

    86. Tolosa JM, Schjenken JE, Clifton VL, Vargas A, Barbeau B, LowryP, Maiti K, Smith R. 2012. The endogenous retroviral envelopeprotein syncytin-1 inhibits LPS/PHA-stimulated cytokine responsesin human blood and is sorted into placental exosomes. Placenta, 33: 933-941.
        doi: 10.1016/j.placenta.2012.08.004

    87. Toufaily C, Lokossou AG, Vargas A, Rassart E, Barbeau B. 2015. A CRE/AP-1-like motif is essential for induced syncytin-2 expressionand fusion in human trophoblast-like model. PLoS One, 10: e0121468.
        doi: 10.1371/journal.pone.0121468

    88. Tristem M. 2000. Identification and characterization of novel humanendogenous retrovirus families by phylogenetic screeningof the human genome mapping project database. J Virol, 74:3715-3730.
        doi: 10.1128/JVI.74.8.3715-3730.2000

    89. Venables PJ, Brookes SM, Griffiths D, Weiss RA, Boyd MT. 1995.Abundance of an endogenous retroviral envelope protein in placentaltrophoblasts suggests a biological function. Virology, 211:589-592.
        doi: 10.1006/viro.1995.1442

    90. Vernochet C, Redelsperger F, Harper F, Souquere S, Catzeflis F, Pierron G, Nevo E, Heidmann T, Dupressoir A. 2014. The capturedretroviral envelope syncytin-A and syncytin-B genes areconserved in the Spalacidae together with hemotrichorial placentation. Biol Reprod, 91: 148.

    91. Vogt VM. 1997. Retroviral Virions and Genomes. In: Retroviruses, Coffin JM, Hughes SH, and Varmus HE (eds). New York: ColdSpring Harbor, pp. 27-69.

    92. Voisset C, Blancher A, Perron H, Mandrand B, Mallet F, Paranhos-Baccala G. 1999. Phylogeny of a novel family of human endogenousretrovirus sequences, HERV-W, in humans and otherprimates. AIDS Res Hum Retroviruses, 15: 1529-1533.
        doi: 10.1089/088922299309810

    93. Wang Z, Zhang Y, Liu S. 2014. [Isolation, culture and identificationof sheep multinucleated chorionic trophoblast cells]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 30: 82-86. (In Chinese)

    94. Wooding FB. 1984. Role of binucleate cells in fetomaternal cellfusion at implantation in the sheep. Am J Anat, 170: 233-250.
        doi: 10.1002/(ISSN)1553-0795

    95. Wooding FB. 1992. Current topic: the synepitheliochorial placentaof ruminants: binucleate cell fusions and hormone production. Placenta, 13: 101-113.
        doi: 10.1016/0143-4004(92)90025-O

    96. Wootton SK, Halbert CL, Miller AD. 2005. Sheep retrovirus structuralprotein induces lung tumours. Nature, 434: 904-907.
        doi: 10.1038/nature03492

    97. Yu H, Liu T, Zhao Z, Chen Y, Zeng J, Liu S, Zhu F. 2014. Mutationsin 3'-long terminal repeat of HERV-W family in chromosome 7upregulate syncytin-1 expression in urothelial cell carcinomaof the bladder through interacting with c-Myb. Oncogene, 33:3947-3958.
        doi: 10.1038/onc.2013.366

    98. Zhang YF, Liu Y, Wang ZJ, Sun XL, Liu SY. 2014. [Research onconstruction of sheep lung adenomas virus pEGFP-C1/exJSRV-env and induction of malignant transformation in NIH3T3].Bing Du Xue Bao, 30: 268-277. (In Chinese)

    99. Zhou H, Li J, Podratz KC, Tipton T, Marzolf S, Chen HB, JiangSW. 2014. Hypomethylation and activation of syncytin-1 gene inendometriotic tissue. Curr Pharm Des, 20: 1786-1795.
        doi: 10.2174/13816128113199990540

    100. Zhuang XW, Li J, Brost BC, Xia XY, Chen HB, Wang CX, JiangSW. 2014. Decreased expression and altered methylation of syncytin-1 gene in human placentas associated with preeclampsia. Curr Pharm Des, 20: 1796-1802.
        doi: 10.2174/13816128113199990541

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    Recent advances in the study of active endogenous retrovirus envelope glycoproteins in the mammalian placenta

      Corresponding author: Shuying Liu,
    • Yufei Zhang, ORCID: 0000-0002-8025-6705
    • College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot 010018, China

    Abstract: Endogenous retroviruses (ERVs) are a component of the vertebrate genome and originate from exogenous infections of retroviruses in the germline of the host. ERVs have coevolved with their hosts over millions of years. Envelope glycoproteins of endogenous retroviruses are often expressed in the mammalian placenta, and their potential function has aroused considerable research interest, including the manipulation of maternal physiology to benefit the fetus. In most mammalian species, trophoblast fusion in the placenta is an important event, involving the formation of a multinucleated syncytiotrophoblast layer to fulfill essential fetomaternal exchange functions. The key function in this process derives from the envelope genes of endogenous retroviruses, namely syncytins, which show fusogenic properties and placenta-specific expression. This review discusses the important role of the recognized endogenous retrovirus envelope glycoproteins in the mammalian placenta.

    • Infectious retroviruses are exogenous retroviruses that have invaded into the host cell, whereby the genomic RNA becomes reverse-transcribed into double-stranded DNA and ultimately inserted into the host cell genome. Such exogenous retrovirus invasion into the germ cells of the host has resulted in a large number of stable retroviral sequences integrated into the host genome that have become part of the host genome(Boeke and Stoye, 1997; Nakaya and Miyazawa, 2015). These retroviruses are collectively referred to as endogenous retroviruses(ERVs). Almost all animal species have ERV sequences in their genomes; for example, ERVs constitute 8% of the human genome(Lander et al., 2001) and 18% of the bovine genome(Adelson et al., 2009).

      The complete ERV genomic structure is similar to the exogenous retroviral genomic structure, generally consisting of 5′-and 3′-long terminal repeats and four structural genes: gag, pro, pol, and env(Herniou et al., 1998; Lokossou et al., 2014). Most ERVs are destined toward annihilation if their expression has detrimental effects for the host. As a consequence, the accumulation of mutations, deletions, rearrangements, and methylation usually result in a replication defect, which has been fine-tuned throughout their evolution in the host genome(Boeke and Stoye, 1997; Black et al., 2010). Although most ERVs are inactivated, some of the ERV genes are also expressed in the host cells(Lokossou et al., 2014; Nakaya and Miyazawa, 2015).

      ERVs show an extraordinary 'affinity' to the placenta based on evidence that ERV particles and mRNAs are often detected in the placenta(Johnson et al., 1990; Harris, 1998; Rote et al., 2004) and that several genes of the host use retroviral promoters to induce placenta-specific transcripts(Rote et al., 2004). Moreover, some envelope genes of ERVs have been found to be essential for the development and formation of the placenta in humans(Mi et al., 2000; Esnault et al., 2008), rabbits(Heidmann et al., 2009), cattle(Adelson et al., 2009), and mice(Dupressoir et al., 2005). Extensive research has confirmed that ERV envelope proteins(termed 'syncytins')promote the cellto-cell fusion of trophoblast cells, and play an important role in the process of syncytiotrophoblast formation in the placenta in primates, rodents, ruminants, lagomorphs, and carnivores(Mi et al., 2000; Frendo et al., 2003; Dupressoir et al., 2009; Dupressoir et al., 2011; Haig, 2012).

      In this review, we focus on the biological roles of ERVs envelope proteins in the development of the placenta. We further discuss the existing controversy in the field and highlight areas of future research and the value of knowledge gained from ERV studies.

    • A retrovirus is an RNA virus whose genome contains at least four genes(gag, pro, pol, and env)(Vogt, 1997). The gag gene encodes the major structural polyprotein Gag, including nucleocapsid(NC), matrix(MA), and capsid(CA), and all elements required to form the viral particle core. The pro gene encodes the viral protease, and is essential for promoting the ripeness of viral particles. The pol gene encodes several products, including reverse transcriptase, RNase H, and integrase. The env gene is essential for the viral surface protein(SU) and transmembrane protein(TM)of the envelope protein(Env), which is responsible for the binding to cellular receptors and membrane fusion. Phylogenetic analyses have classified all known retroviruses into three broad groups(Tristem, 2000; Gifford and Tristem, 2003; Henzy and Johnson, 2013). Here, we focus on ERVs of class Ⅰ(epsilonretroviruses, betaretroviruses, and their associated ERVs) and class Ⅱ(alpharetroviruses, betaretroviruses, lentiviruses, and their associated ERVs), as well as on the structure and function of Env proteins(Benit et al., 2001; Katzourakis et al., 2009; Henzy and Johnson, 2013).

      The Env proteins of endogenous and exogenous retroviruses are similar. The retroviral Env protein is translated in the host cell where it presents as a trimer precursor in the endoplasmic reticulum. After being transported to the Golgi apparatus, the trimer precursor is cleaved into two subunits, SU and TM, by the host's protease. They combine through non-covalent binding, as in the case of betaretroviruses and lentiviruses, or by virtue of a single intersubunit disulfide bond, as observed in gamma-, delta-and alpha-retroviruses(Leamnson and Halpern, 1976; Pinter et al., 1978; Kowalski et al., 1987; Smith and Cunningham, 2007; Li et al., 2008; Henzy and Coffin, 2013; Henzy and Johnson, 2013). The Env trimers become fixed on the cellular membrane via the TM subunit(Swanstrom and Wills, 1997), whereas the majority of the SU is exposed to the host immune system. The SU includes a signal peptide and a receptor-binding domain. There is a cleavage site between the SU and TM subunits comprising a polybasic motif(K / R-X -K / R -R)(Hosaka et al., 1991); this sequence also marks the beginning of the TM region(Henzy and Johnson, 2013). There are two hydrophobic domains in the TM subunit: the first domain forms the fusion peptide at or near the N-terminus, and the second is the membrane-spanning region. The ectodomain contains two heptad-repeat regions(hr1 and hr2), which are essential components for trimer formation and the dynamic rearrangement during the process of fusion, and form the highly conserved coiled-coil structure that is observed in many viral envelope proteins(Li et al., 2008). The ectodomain sequence of some retroviruses contains a recognized immunosuppressive domain(ISD)(Benit et al., 2001). The transmembrane region of the C-terminal is the cytoplasmic tail region, which is located in the cytoplasm of the host cell membrane before virus particle assembly and on the inner side of the membrane after assembly.

      Within the Env trimer at the surface of the viral particle, the SU maintains the TM in a metastable conformation that is similar to a 'spring-loaded' model(Henzy and Coffin, 2013). Therefore, during the invasion process, the virion of retroviruses makes contact with the host cell via the SU, which binds to its receptor on the target cell(Goff, 2001; Hofacre and Fan, 2010). The virus particles make contact with the host's cell surface-specific receptors via the SU subunit of the Env protein when the retrovirus invades the host cell. Binding of the SU subunit to the receptor induces a conformational change that enables SU to be exposed to the TM subunit so that the fusion peptide is inserted into the cell membrane. This causes the TM subunits to fold into a highly stable trimer-shaped 'hairpin' structure, thereby causing the alpha-helical coiled-coils of hr1 and hr2 to make contact(Henzy and Johnson, 2013). As Env trimers transition from a metastable state to a stable state, the released energy drives the fusion of the cellular and viral membranes(Swanstrom and Wills, 1997). The envelope protein of ERVs uses the same mechanism to promote the fusion of trophoblast cells for formation of the placental syncytial layer. The ISD within the TM subunit allows for the virus particles to escape from the host immune system. Specifically, several studies have indicated that the ISD in the TM subunit of the envelope protein of ERVs can inhibit the mother's immune system from attacking against a fetus(Hosaka et al., 1991; Singh et al., 1999; Hofacre and Fan, 2010; Haig, 2013).

      The envelope of ERVs have been frequentlydetected in the reproductive tract and placenta, and appear to show a specific preference to the placenta(Bierwolf et al., 1975; Kalter et al., 1975; Imamura et al., 1976; Smith and Moore, 1988; Harris, 1991; DeHaven et al., 1998; Haig, 2013). This affinity has piqued the interest of many researchers into discovering the possible function of active endogenous retroviruses in the placenta. Some researchers have suggested that retroviral promoters play a significant role in placental development(Harris, 1991; DeHaven et al., 1998; Harris, 1998). In particular, it has been proposed that placental trophoblastic cells create a comfortable and suitable environment for ERV activity, and the placenta has become 'addicted' to taking advantage of ERV-derived promoters in the course of its developmental process(Chuong, 2013; Haig, 2013). Some of other scientists insist that retroviral genes have been adopted for several placental functions(Dolei et al., 2015). In fact, independent capture events have been confirmed in primates, rodents, ruminants, carnivores, and lagomorphs, showing the participation of retroviral genes in the formation of the syncytium layer via trophoblast cellcell fusion at the fetomaternal interface(Cornelis et al., 2013). In the following sections we will present the current status of research on ERV envelope genes that have been integrated into the placenta of different species, and their potential function in reproductive biology.

    • The human placenta shows the highest levels of human endogenous retroviruses(HERVs)among all normal tissues(Tolosa et al., 2012). The env genes of the HERVs HERV-W(ERVWE1), HERV-FRD, and ERV-3 were found to be abundantly expressed in the human placenta(Venables et al., 1995; Blond et al., 2000; de Parseval et al., 2003; Black et al., 2010; Tolosa et al., 2012). In 1999, Blond et al. first reported that the ERVWE1 gene was expressed in syncytiotrophoblast cells, which was subsequently given the name syncytin-1 by Mi et al. in 2000(Blond et al., 1999; Mi et al., 2000). Syncytin-1 is an ERVWE1 envelope gene located on human chromosome 7. ERVWE1 belongs to the HERV-W lineage that is estimated to have invaded the genomes of higher primates about 25 to 40 million years ago based on phylogenetic analyses(Voisset et al., 1999; Blond et al., 2000). The syncytiotrophoblast of the mammalian placenta is a true syncytium, derived from the fusion between progenitor cytotrophoblasts cells. The syncytiotrophoblast acts as an epithelial barrier that makes direct contact with maternal blood and transports key nutrients and other solutes to the fetus for its development(Omata et al., 2013).

      Syncytin-1 was recently demonstrated to be a highly fusogenic membrane glycoprotein with characteristics of retroviral Env protein(Figure 1) (Bjerregaard et al., 2014; Bjerregard et al., 2014; Huang et al., 2014a; Huang et al., 2014b). Syncytin-1 induces the formation of syncytia in the interaction with sodium-dependent neutral amino acid transporter 2(ASCT2)(Frendo et al., 2003; Tolosa et al., 2012). A large number of recent in vitro studies have indicated that syncytial-1 is involved in the cellular fusion of human trophoblast cells, which may play a key role in the formation of human placenta(Mi et al., 2000; Tolosa et al., 2012). Transfection of syncytin-1 of multiple cell lineages has been shown to induce cellular fusion; in addition, cells treated with an antibody against the syncytin-1 protein resulted in a significant decrease in cell fusion(Blond et al., 1999; Mi et al., 2000; Frendo et al., 2003; Black et al., 2010). Moreover, direct inhibition of the expression of syncytin-1 inhibited the fusion of trophoblastic cells(Frendo et al., 2003). Other studies have shown that the expression of syncytin-1 mRNA in pathological placentas is very low(Huang et al., 2014b; Yu et al., 2014; Zhou et al., 2014; Zhuang et al., 2014; Machnik et al., 2015; Tolosa et al., 2015).

      Figure 1.  Schematic diagram of the functional domains of Env glycoproteins proposed to be involved in placental morphogenesis. SU, surface subunit; TM, transmembrane subunit; SP, signal peptide; RBD, receptor binding domain; FP, fusion peptide; ISD, immunosuppressive domain; MSR, membrane-spanning region; CT, cytoplasmic tail; gray and blue color parts, linker regions.

      Syncytin-2 is the envelope gene of HERV-FRD, and is also abundantly expressed in the human placenta(Esnault et al., 2008; Cornelis et al., 2015; Nakaya and Miyazawa, 2015; Toufaily et al., 2015). Similar to syncytin-1, transient transfection of syncytin-2 induced cell fusion in a variety of cell lines(Knerr et al., 2002; Black et al., 2010). The interaction of syncytin-2 and the major facilitator superfamily domain-containing 2 receptor promoted the cell fusion of human trophoblast cells(Machnik et al., 2015). Syncytin-2 is similar to syncytin-1 in structure, but they have different immunosuppressive properties(Figure 1) (Mangeney et al., 2007; Black et al., 2010).

      ERV-3 is also expressed in trophoblast cells and syncytiotrophoblasts, but a premature stop codon in its long open reading frame has resulted in loss of the transmembrane region and other functional areas(Cohen et al., 1985; Boyd et al., 1993). The Env protein of ERV-3 does not elicit cell fusion(Lin et al., 1999). However, ERV-3 is stably expressed in trophoblast cells, and was shown to induce trophoblast differentiation and increase the levels of chorionic gonadotropin(Harris, 1998). Furthermore, ERV3 Env is also expressed in many normal tissues, especially in hormone-producing organs, including the adrenal and sebaceous glands and testis(Harris, 1998; Black et al., 2010). These findings suggest that it may play a critical role in the process of hormone secretion.

    • In 2005, Dupressoir et al.(2005) conducted a systematic in silico search of the entire mouse genome database and identified two fully coding envelope genes that were unique and independent of any known murine endogenous retrovirus, which were named syncytin-A and -B(Figure 1). Syncytin-A and -B are orthologous genes whose expression is conserved in all muridae tested(mouse, rat, gerbil, vole, and hamster), and are estimated to have entered the rodent lineage at least 40 million years ago(Dupressoir et al., 2005; Black et al., 2010; Vernochet et al., 2014; Cornelis et al., 2015). Quantitative reverse transcription-polymerase chain reaction analyses con firmed that the two genes are specifically expressed in the placenta, and in situ hybridization of placenta cryosections revealed that the two genes are specifically expressed in trophoblast cells and the syncytia layer(Dupressoir et al., 2005). In vitro transfection experiments showed that both genes can induce cell–cell fusion, but that they use different receptors(Dupressoir et al., 2005). Another study by the same group showed that homozygous syncytin-A null mouse embryos of syncytin-A knock-out mice died in utero between 11.5 and 13.5 days of gestation(Dupressoir et al., 2009). In another experiment, use of a specific antibody and antisense oligonucleotides to inhibit the expression of syncytin-A, caused marked reduction in the formation of syncytiotrophoblast cells(Gong et al., 2007). In addition, trophoblast cells cultured with syncytin-A in vitro promoted syncytiotrophoblast cell development within 24 h, strongly suggesting that syncytin-A is a fusogenic protein that plays an important regulatory role(Henke et al., 2013). These results indicate that syncytin-A is essential to the process of rodent trophoblast cell differentiation and syncytiotrophoblast formation. Both syncytin-A and -B contain a recognized immunosuppressive region, leading some researchers to suggest that they may also play a role in maternal-fetal tolerance, although there is no strong confirmatory evidence(Black et al., 2010). In 2011, Dupressoir et al. knocked out the syncytin-B gene in the mouse genome, and found that these syncytial-B-deficient mice could complete a pregnancy, but fetal growth was retarded and the number of newborns was reduced compared to wild-type mice(Dupressoir et al., 2011).

    • In 2009, Heidmann et al. conducted a systematic in silico search of full-length env genes with an uninterrupted open reading frame within the rabbit genome, and found an env gene of retroviral origin with the characteristic features of syncytin, which was named syncytin-Ory1(Figure 1). They further confirmed that the syncytin-Ory1 gene was specifically expressed in and had entered the Lagomorpha order approximately 12–30 million years ago(Heidmann et al., 2009). The results of in situ hybridization showed that syncytin-Ory1 mRNA was specifically expressed in the rabbit placenta junctional zone, where fetal tissue invades the maternal uterus decidua to form the labyrinth trophoblast. Surprisingly, the Syncytin-Ory1 receptor was found to be ASCT2, the same receptor for syncytin-1, as mentioned above(Black et al., 2010). These results demonstrated that syncytin-Ory1 likely plays an important role in formation of the rabbit placenta(Heidmann et al., 2009; Black et al., 2010).

    • Recent studies have shown that the ERV env gene is expressed in the bovine placenta(Nakagawa et al., 2013). bERVE-A possesses a sequence that is similar to the sequence of human syncytin-1, and is specifically expressed in the bovine placental trophoblast, but does not have the entire open reading frame(Henzy and Coffin, 2013; Tolosa et al., 2015). In order to determine the derived function of ERV env genes in bovine placenta development, Nakagawa et al.(2013) used a high-throughput sequencer to examine the transcription status of ENV derived env genes during different cattle pregnancy implantation periods. The results showed that about 18% of the total expression of the ERV env gene was expressed in the process of bovine placenta formation(Nakagawa et al., 2013). Finally, they succeeded in finding three env-derived genes with a long open reading frame that were highly expressed in trophoblast cell lines. However, the biological function of these ERV genes in the bovine placenta has not yet been reported. To date, only the env genes of the bovine ERVs BERV-K1 and BERV-K2 have been well studied, which were found to be abundantly expressed in the bovine placenta and bovine trophoblast cell lines cultivated in vitro(Baba et al., 2011; Koshi et al., 2012; Nakaya et al., 2013). Here, we focus on the BERV-K1 envelope glycoprotein Fematrin-1, which is specifically expressed in bovine trophoblast cells. Fematrin-1 was shown to induce cell fusion of both trophoblast and bovine endometrial cells in vitro(Nakaya et al., 2013). Fematrin-1 was found to have integrated into intron 18 of bovine FAT tumor suppressor homolog 2(FAT2)approximately 18.3–25.4 million years ago(Nakaya et al., 2013; Tolosa et al., 2015).

    • The domestic sheep genome includes at least 27 copies of endogenous beta-retroviruses, which are closely related to the exogenous and pathogenic JSRV, and were thus named enJSRVs(Palmarini et al., 2004; Arnaud et al., 2007; Arnaud et al., 2010; Black et al., 2010; Armezzani et al., 2011). JSRV is the causative agent of ovine pulmonary adenocarcinoma, an infectious lung tumor disease in sheep(Hofacre and Fan, 2010). JSRV is distinct from other oncogenic retroviruses, because its envelope protein can induce cell carcinogenesis both in vivo and vitro(Maeda et al., ; Allen et al., 2002; Danilkovitch-Miagkova et al., 2003; Liu and Miller, 2005; Wootton et al., 2005; Hofacre and Fan, 2010; Zhang et al., 2014). However, the mechanism of JSRV Env-induced cell transformation is not entirely clear. Interestingly, many enJSRVs encode functional viral proteins, and many enJSRVs Env glycoproteins are quite similar to JSRV Env glycoprotein(Black et al., 2010; Spencer and Palmarini, 2012). However, enJSRVs Env glycoprotein(Figure 1)does not cause cancer and it does not induce the transformation of cells(Hull et al., 2012; Armezzani et al., 2014).

      Interestingly, enJSRV env and hyaluronoglucosaminidase 2(HYAL2), a cellular receptor for both JSRV and enJSRVs Env, are abundantly expressed in the trophoblast giant binucleate cells(BNCs) and multinucleated plaques of the syncytiotrophoblast within the placentomes(Figure 2)during pregnancy(Wooding, 1984; Wooding, 1992; Guillomot, 1995; Roberts et al., 1999; Spencer et al., 2004; Dunlap et al., 2005; Black et al., 2010; Spencer and Palmarini, 2012; Qi et al., 2012). These findings have piqued interest in enJSRV env, given that it may play an important physiological role in conceptus elongation and the onset of the differentiation of trophoblast giant BNCs. In one study, morpholino was injected into the ewe uterus on day 8 of pregnancy, which inhibited the translation of enJSRV envelope protein(Dunlap et al., 2006; Black et al., 2010; Spencer and Palmarini, 2012). The results showed that through the injection of morpholino in ewes at 16 days of gestation, the growth of trophectoderm cells was inhibited and the number of trophoblast giant BNCs was reduced. These results led to the hypothesis that en-JSRVs and its receptor HYAL2 promote the growth and differentiation of sheep placental syncytium trophoblastic cells(Spencer et al., 2007; Black et al., 2010; Spencer and Palmarini, 2012).

      Figure 2.  Structure of the synepitheliochorial placenta of sheep. (A) Schematic drawing of the sheep fetus and placenta in utero. (B, C) Hematoxylin-and-eosin stained placenta sections of sheep.

      However, Cornelis et al.(2013) identified an envelope gene from the genome of sheep and cattle that shows specific expression in the Ovis aries and the Bos taurus placenta, which was named syncytin-Rum1(Figure 1). Syncytin-Rum1 is estimated to have integrated into the genome of ruminants approximately 30 Mya. The syncytin-Rum1 gene exhibits all of the typical characteristics of a syncytin gene: (ⅰ) it is specifically expressed in the placenta; and (ⅱ) it exhibits fusogenic activity by mediating cell–cell fusion (Cornelis et al., 2013). This discovery led to speculation about the veracity of the hypothesis on the effect of enJSRVs and HYAL2 on the growth and differentiation of sheep placental syncytium trophoblastic cells, because enJSRV Env is expressed in the placentabut not specifically, and there is no conclusive evidence that it shows cell–cell fusion activity. Therefore, further research on the enJSRV Env protein function and its function in reproductive biology is required. Our research group has cultured sheep trophoblast cells and cloned the enJSRV env gene. We have further established an RNA interference plasmid of targeted enJSRV env and measured its interference efficiency (Wang et al., 2014). We are next planning to up-regulate and inhibit the expression of enJSRV env gene in sheep trophoblast cells in vitro to evaluate the enJSRV Env protein function and its effect on reproductive biology. These results should help to verify the authenticity of the hypothesis.

    • The findings described above clearly demonstrate that capturing of ERV-derived genes has repeatedly occurred throughout the evolution of placental mammals, suggesting that new syncytin genes will be found in the syncytiotrophoblast organization of other placental mammals(Heidmann et al., 2009). Indeed, recent investigations in other animals such as Marmota(woodchuck) and Carnivora(dogs and cats)strongly support this hypothesis. Cornelis et al.(2012) searched for full-length coding envelope protein genes within the dog and cat genomes, and found a common gene in both species named syncytin-Car1 that displayed placenta-specific expression(Figure 1). The syncytin-Car1 gene was cloned into a cytomegalovirus-driven expression vector, and a transient transfection experiment showed that the gene displays characteristic cell fusion activity. This gene is the oldest syncytin gene identified to date, and is estimated to have integrated into the carnivorous animal genome between approximately 60 and 85 Mya(Cornelis et al., 2012). Recently, Redelsperger et al.(2014) discovered an ERV envelope gene with all the characteristic features of a syncytin. This gene is specifically expressed in the woodchuck placenta and was named syncytin-Mar1, and was shown to induce cell-cell fusion in vivo, indicating an essential role in its host's physiology. Syncytin-Mar1(Figure 1)has gone through about 25 Mya of evolution, but is not related to any of the other syncytins identified to date. In addition, Cornelis et al.(2015) also found a similar syncytin gene in the placenta of marsupials, which was named syncytin-Opol. Syncytin-Opo1 could also induce cell fusion in vitro, but does not show high expression in the placenta of marsupials.

    • Most scientists believe that the placenta evolved into an environment where retroviral genes were 'tamed' to serve functions that benefit the host, including the manipulation of maternal physiology for protecting the fetus (Haig, 2012). Chuong (Chuong, 2013) suggested that ERV-mediated regulatory evolution is, and will continue to be, an important mechanism of the evolution of placental development. The evolutionary interplay between retroviruses and host defense may contribute to the significant differences observed among mammalian placentas. Many recent studies have focused on the capture of ERVderived genes for specific functional adaptations in the placenta. Syncytin genes within the mammalian placenta(e.g., syncytin-1 and syncytin-2 in humans, syncytin-A and syncytin-B in Muroidea, syncytin-Ory1 in Leporidae, syncytin-Car1 in Carnivora, and the syncytin-Rum1 in ruminants)illustrate this point nicely. However, the exact mechanism by which the ERV env genes promote placenta differentiation and trophoblast cell fusion remains unclear. In addition, as an important protein for sheep placenta development, the specific function of enJSRV Env is also unclear and requires much more research effort. Overall, studies with enJSRVs and JSRV as well as other ERVs expressed in the placenta have helped us to comprehend how ERVs evolved from infectious elements to essential genes.

    • This report was funded by the National Natural Science Foundation of China(31360597 and 31160493), the doctoral fund project of Ministry of Education(20111515110008) and Inner Mongolia technology application research project(20130224).

    • The authors declare that they have no conflict of interinterest. This article does not contain any studies with human or animal subjects performed by any of the authors.

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