Skip to main content

Roles of Endogenous Retrovirus-Encoded Syncytins in Human Placentation

  • Chapter
  • First Online:
Human Retrotransposons in Health and Disease

Abstract

Syncytin-1 and Syncytin-2 are two human endogenous retroviral glycoproteins that are expressed in the human placenta. In this tissue, both proteins play important roles in the development of a healthy and functional placenta. Indeed, the conserved fusogenic properties that characterize Syncytin proteins among the mammalian clade are believed to be crucial for the formation of the syncytiotrophoblast (STB) layer of the placenta. Moreover, human Syncytins harbor functional immunosuppressive domains, which could be implicated in the regulation of the maternal immune system during pregnancy. Similar results have been described for the equivalent murine Syncytin-A and -B in terms of their essential placental function. Furthermore, the biological function of Syncytin-1 and -2 might be linked through their presence on the surface of small extracellular vesicles, including exosomes. As important proteins for the development of the placenta, dysregulation of Syncytin-1 and -2 expression is linked to different pathologies, such as preeclampsia and HELLP syndrome. Human Syncytins are also associated to other diseases. Hence, the abnormal expression of these placenta-specific fusogenic proteins in other tissues has been linked to several different types of cancers. As Syncytin-1 and -2 are associated to exosomes, their levels could be monitored through analyses of blood-derived exosomes and thereby be used for early diagnosis of placental disorder or potentially monitoring the progression or aggressiveness of various cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Bibliography

  • Abildgaard U, Heimdal K (2013) Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. Eur J Obstet Gynecol Reprod Biol 166:117–123

    Article  CAS  PubMed  Google Scholar 

  • Anderson MJ, Stanbridge EJ (1993) Tumor suppressor genes studied by cell hybridization and chromosome transfer. Faseb J 7:826–833

    CAS  PubMed  Google Scholar 

  • Atay S, Gercel-Taylor C, Suttles J, Mor G, Taylor DD (2011) Trophoblast-derived exosomes mediate monocyte recruitment and differentiation. Am J Reprod Immunol 65:65–77

    Article  CAS  PubMed  Google Scholar 

  • Babst M (2011) MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between. Curr Opin Cell Biol 23:452–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bjerregaard B, Holck S, Christensen IJ, Larsson LI (2006) Syncytin is involved in breast cancer-endothelial cell fusions. Cell Mol Life Sci 63:1906–1911

    Article  CAS  PubMed  Google Scholar 

  • Blaise S, de Parseval N, Benit L, Heidmann T (2003) Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc Natl Acad Sci U S A 100:13013–13018

    Google Scholar 

  • Blaise S, de Parseval N, Heidmann T (2005) Functional characterization of two newly identified Human Endogenous Retrovirus coding envelope genes. Retrovirology 2:19

    Google Scholar 

  • Blond JL, Besème F, Duret L, Bouton O, Bedin F, Perron H, Mandrand B, Mallet F (1999) Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J Virol 73:1175–1185

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-Fernandes S, Mandrand B, Mallet F, Cosset FL (2000) An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol 74:3321–3329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borzychowski AM, Sargent IL, Redman CW (2006) Inflammation and pre-eclampsia. Semin Fetal Neonatal Med 11:309–316

    Article  CAS  PubMed  Google Scholar 

  • Buslei R, Strissel PL, Henke C, Schey R, Lang N, Ruebner M, Stolt CC, Fabry B, Buchfelder M, Strick R (2015) Activation and regulation of endogenous retroviral genes in the human pituitary gland and related endocrine tumours. Neuropathol Appl Neurobiol 41:180–200

    Article  CAS  PubMed  Google Scholar 

  • Carr MC (1967) Biology of human trophoblast. Calif Med 107:338–343

    CAS  PubMed  PubMed Central  Google Scholar 

  • Carter AM, Enders AC (2004) Comparative aspects of trophoblast development and placentation. Reprod Biol Endocrinol 2:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chang C, Chen PT, Chang GD, Huang CJ, Chen H (2004) Functional characterization of the placental fusogenic membrane protein syncytin. Biol Reprod 71:1956–1962

    Article  CAS  PubMed  Google Scholar 

  • Chen CP, Wang KG, Chen CY, Yu C, Chuang HC, Chen H (2006) Altered placental syncytin and its receptor ASCT2 expression in placental development and pre-eclampsia. BJOG 113:152–158

    Article  PubMed  Google Scholar 

  • Chen CP, Chen LF, Yang SR, Chen CY, Ko CC, Chang GD, Chen H (2008) Functional characterization of the human placental fusogenic membrane protein syncytin 2. Biol Reprod 79:815–823

    Article  CAS  PubMed  Google Scholar 

  • Cheng YH, Handwerger S (2005) A placenta-specific enhancer of the human syncytin gene. Biol Reprod 73:500–509

    Article  CAS  PubMed  Google Scholar 

  • Cheng YH, Richardson BD, Hubert MA, Handwerger S (2004) Isolation and characterization of the human syncytin gene promoter. Biol Reprod 70:694–701

    Article  CAS  PubMed  Google Scholar 

  • Cheynet V, Ruggieri A, Oriol G, Blond JL, Boson B, Vachot L, Verrier B, Cosset FL, Mallet F (2005) Synthesis, assembly, and processing of the Env ERVWE1/syncytin human endogenous retroviral envelope. J Virol 79:5585–5593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheynet V, Oriol G, Mallet F (2006) Identification of the hASCT2-binding domain of the Env ERVWE1/syncytin-1 fusogenic glycoprotein. Retrovirology 3:41

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chiang M-H, Liang F-Y, Chen CP, Chang CW, Cheong ML, Wang LJ, Liang C-Y, Lin F-Y, Chou CC, Chen H (2009) Mechanism of hypoxia-induced GCM1 degradation. Implications for the pathogenesis of preeclampsia. J Biol Chem 284:17411–17419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cornelis G, Heidmann O, Bernard-Stoecklin S, Reynaud K, Véron G, Mulot B, Dupressoir A, Heidemann T (2012) Ancestral capture of syncytin-Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora. Proc Natl Acad Sci U S A 109:E432–E441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cornelis G, Heidmann O, Degrelle S, Vernochet C, Lavialle C, Letzelter C, Bernard-Stoecklin S, Hassanin A, Mulot B, Guillomot M, Hue I, Heidmann T, Dupressoir A (2013) Captured retroviral envelope syncytin gene associated with the unique placental structure of higher ruminants. Proc Natl Acad Sci U S A 110:E828–E837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cornelis G, Vernochet C, Malicorne S, Souquere S, Tzika A, Goodman S, Catzeflis F, Robinson T, Milinkovitch M, Pierron G, Heidmann O, Dupressoir A, Heidmann T (2014) Retroviral envelope syncytin capture in an ancestrally diverged mammalian clade for placentation in the primitive Afrotherian tenrecs. Proc Natl Acad Sci U S A 111:E4332–E4341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cornelis G, Vernochet C, Carradec Q, Souquere S, Mulot B, Catzeflis F, Nilsson MA, Menzies BR, Renfree MB, Pierron G, Zeller U, Heidmann O, Dupressoir A, Heidmann T (2015) Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials. Proc Natl Acad Sci U S A 112:E487–E496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Costa MA (2016) The endocrine function of human placenta: an overview. Reprod Biomed Online 32:14–43

    Article  CAS  PubMed  Google Scholar 

  • Cui L, Wang H, Lu X, Wang R, Zheng R, Li Y, Yang X, Jia WT, Zhao Y, Wang Y, Wang H, Wang YL, Zhu C, Lin HY, Wang H (2016) Effects of individually silenced N-glycosylation sites and non-synonymous single-nucleotide polymorphisms on the fusogenic function of human syncytin-2. Cell Adh Migr 10(1–2):39–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Parseval N, Heidmann T (1998) Physiological knockout of the envelope gene of the single-copy ERV-3 human endogenous retrovirus in a fraction of the Caucasian population. J Virol 72:3442–3445

    PubMed  PubMed Central  Google Scholar 

  • De Parseval N, Heidmann T (2005) Human endogenous retroviruses: from infectious elements to human genes. Cytogenet Genome Res 110:318–332

    Article  PubMed  CAS  Google Scholar 

  • De Parseval N, Lazar V, Casella JF, Benit L, Heidmann T (2003) Survey of human genes of retroviral origin: identification and transcriptome of the genes with coding capacity for complete envelope proteins. J Virol 77:10414–10422

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Denzer K, Kleijmeer MJ, Heijnen HFJ, Stoorvogel W, Geuze HJ (2000a) Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 113:3365–3374

    CAS  PubMed  Google Scholar 

  • Denzer K, VAN Eijk M, Kleijmeer MJ, Jakobson E, DE Groot C, Geuze HJ (2000b) Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol 165:1259–1265

    Article  CAS  PubMed  Google Scholar 

  • Dewannieux M, Heidmann T (2013) Endogenous retroviruses: acquisition, amplification and taming of genome invaders. Curr Opin Virol 3:646–656

    Article  CAS  PubMed  Google Scholar 

  • Duley L (2009) The global impact of pre-eclampsia and eclampsia. Semin Perinatol 33:130–137

    Article  PubMed  Google Scholar 

  • Dupressoir A, Marceau G, Vernochet C, Benit L, Kanellopoulos C, Sapin V, Heidmann T (2005) Syncytin-A and syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae. Proc Natl Acad Sci U S A 102:725–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dupressoir A, Vernochet C, Bawa O, Harper F, Pierron G, Opolon P, Heidmann T (2009) Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene. Proc Natl Acad Sci U S A 106:12127–12132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dupressoir A, Vernochet C, Harper F, Guégan J, Dessen P, Pierron G, Heidmann T (2011) A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc Natl Acad Sci U S A 108:E1164–E1173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dupressoir A, Lavialle C, Heidmann T (2012) From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta 33:663–671

    Article  CAS  PubMed  Google Scholar 

  • Dusse LM, Alpoim PN, Silva JT, Rios DR, Brandao AH, Cabral AC (2015) Revisiting HELLP syndrome. Clin Chim Acta 451:117–120

    Article  CAS  PubMed  Google Scholar 

  • Esnault C, Priet S, Ribet D, Vernochet C, Bruls T, Lavialle C, Weissenbach J, Heidmann T (2008) A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2. Proc Natl Acad Sci U S A 105:17532–17537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esnault C, Cornelis G, Heidmann O, Heidmann T (2013) Differential evolutionary fate of an ancestral primate endogenous retrovirus envelope gene, the EnvV syncytin, captured for a function in placentation. PLoS Genet 9:e1003400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fischer SJ (2015) Why is placentation abnormal in preeclampsia? Am J Obstet Gynecol 213(4 Suppl):S115–S122

    Article  Google Scholar 

  • Frendo JL, Olivier D, Cheynet V, Blond JL, Bouton O, Vidaud M, Rabreau M, Evain-Brion D, Mallet F (2003) Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cell Biol 23:3566–3574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furukawa S, Kuroda Y, Sugiyama A (2014) A comparison of the histological structure of the placenta in experimental animals. J Toxicol Pathol 27:11–18

    Article  PubMed  PubMed Central  Google Scholar 

  • Gerbaud P, Pidoux G (2015) Review: an overview of molecular events occurring in human trophoblast fusion. Placenta 36(Suppl 1):S35–S42

    Article  CAS  PubMed  Google Scholar 

  • Haram K, Mortensen JH, Nagy B (2014) Genetic aspects of preeclampsia and the HELLP syndrome. J Pregnancy 2014:1–13

    Article  CAS  Google Scholar 

  • Hedlund M, Stenqvist AC, Nagaeva O, Kjellberg L, Wulff M, Baranov V, Mincheva-Nilsson L (2009) Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function. J Immunol 183:340–351

    Article  CAS  PubMed  Google Scholar 

  • Heidmann O, Vernochet C, Dupressoir A, Heidmann T (2009) Identification of an endogenous retroviral envelope gene with fusogenic activity and placenta-specific expression in the rabbit: a new “syncytin” in a third order of mammals. Retrovirology 6:107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Holder BS, Tower CL, Abrahams VM, Aplin JD (2012a) Syncytin-1 in the human placenta. Placenta 33:460–466

    Article  CAS  PubMed  Google Scholar 

  • Holder BS, Tower CL, Forbes K, Mulla MJ, Aplin JD, Abrahams VM (2012b) Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1. Immunology 136:184–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Q, Chen H, Li J, Oliver M, Ma X, Byck D, Gao Y, Jiang SW (2014a) Epigenetic and non-epigenetic regulation of syncytin-1 expression in human placenta and cancer tissues. Cell Signal 26:648–656

    Article  CAS  PubMed  Google Scholar 

  • Huang Q, Chen H, Wang F, Brost BC, Li J, Gao Y, Li Z, Gao Y, Jiang SW (2014b) Reduced syncytin-1 expression in choriocarcinoma BeWo cells activates the calpain1-AIF-mediated apoptosis, implication for preeclampsia. Cell Mol Life Sci 71:3151–3164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hummel J, Kammerer U, Muller N, Avota E, Schneider-Schaulies S (2015) Human endogenous retrovirus envelope proteins target dendritic cells to suppress T-cell activation. Eur J Immunol 45:1748–1759

    Article  CAS  PubMed  Google Scholar 

  • Kato N, Pfeifer-Ohlsson S, Kato M, Larsson E, Rydnert J, Ohlsson R, Cohen M (1987) Tissue-specific expression of human provirus ERV3 mRNA in human placenta: two of the three ERV3 mRNAs contain human cellular sequences. J Virol 61:2182–2191

    CAS  PubMed  PubMed Central  Google Scholar 

  • Khong TY (2004) Placental vascular development and neonatal outcome. Semin Neonatol 9:255–263

    Article  PubMed  Google Scholar 

  • Kjeldbjerg AL, Villesen P, Aagaard L, Pedersen FS (2008) Gene conversion and purifying selection of a placenta-specific ERV-V envelope gene during simian evolution. BMC Evol Biol 8:266

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Knerr I, Beinder E, Rascher W (2002) Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome. Am J Obstet Gynecol 186:210–213

    Article  CAS  PubMed  Google Scholar 

  • Knerr I, Huppertz B, Weigel C, Dotsch J, Wich C, Schild RL, Beckmann MW, Rascher W (2004) Endogenous retroviral syncytin: compilation of experimental research on syncytin and its possible role in normal and disturbed human placentogenesis. Mol Hum Reprod 10:581–588

    Article  CAS  PubMed  Google Scholar 

  • Kudaka W, Oda T, Jinno Y, Yoshimi N, Aoki Y (2008) Cellular localization of placenta-specific human endogenous retrovirus (HERV) transcripts and their possible implication in pregnancy-induced hypertension. Placenta 29:282–289

    Article  CAS  PubMed  Google Scholar 

  • Kudo Y, Boyd CAR, Sargent IL, Redman CWG (2003) Hypoxia alters expression and function of syncytin and its receptor during trophoblast cell fusion of human placental BeWo cells: implications for impaired trophoblast syncytialisation in pre-eclampsia. Biochim Biophys Acta 1638:63–67

    Article  CAS  PubMed  Google Scholar 

  • Lacroix MC, Guibourdenche J, Frendo JL, Pidoux G, Evain-Brion D (2002) Placental growth hormones. Endocrine 19:73–79

    Article  CAS  PubMed  Google Scholar 

  • Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, EL Oakley RM, Pasterkamp G, DE Kleijn DP, Lim SK (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222

    Article  CAS  PubMed  Google Scholar 

  • Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, Fitzhugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, Levine R, McEwan P, Mckernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann Y, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, Mcmurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, Mcpherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    Article  CAS  PubMed  Google Scholar 

  • Langbein M, Strick R, Strissel PL, Vogt N, Parsch H, Beckmann MW, Schild RL (2008) Impaired cytotrophoblast cell–cell fusion is associated with reduced syncytin and increased apoptosis in patients with placental dysfunction. Mol Reprod Dev 75:175–183

    Article  PubMed  CAS  Google Scholar 

  • Larsen JM, Christensen IJ, Nielsen HJ, Hansen U, Bjerregaard B, Talts JF, Larsson LI (2009) Syncytin immunoreactivity in colorectal cancer: potential prognostic impact. Cancer Lett 280:44–49

    Article  CAS  PubMed  Google Scholar 

  • Larsson L-I, Bjerregaard B, Wulf-Andersen L, Talts JF (2007a) Syncytin and cancer cell fusions. Sci World J 7:1193–1197

    Article  CAS  Google Scholar 

  • Larsson LI, Holck S, Christensen IJ (2007b) Prognostic role of syncytin expression in breast cancer. Hum Pathol 38:726–731

    Article  CAS  PubMed  Google Scholar 

  • Lavialle C, Cornelis G, Dupressoir A, Esnault C, Heidmann O, Vernochet C, Heidmann T (2013) Paleovirology of ‘syncytins’, retroviral env genes exapted for a role in placentation. Philos Trans R Soc Lond B Biol Sci 368:20120507

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lavillette D, Marin M, Ruggieri A, Mallet F, Cosset FL, Kabat D (2002) The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors. J Virol 76:6442–6452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee X, Keith JC Jr, Stumm N, Moutsatsos I, McCoy JM, Crum CP, Genest D, Chin D, Ehrenfels C, Pijnenborg R, Van Assche FA, Mi S (2001) Downregulation of placental syncytin expression and abnormal protein localization in pre-eclampsia. Placenta 22:808–812

    Article  CAS  PubMed  Google Scholar 

  • Li F, Nellaker C, Sabunciyan S, Yolken RH, Jones-Brando L, Johansson AS, Owe-Larsson B, Karlsson H (2014) Transcriptional derepression of the ERVWE1 locus following influenza A virus infection. J Virol 88:4328–4337

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liang CY, Wang LJ, Chen CP, Chen LF, Chen YH, Chen H (2010) GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biol Reprod 83:387–395

    Article  CAS  PubMed  Google Scholar 

  • Lokossou AG, Toudic C, Barbeau B (2014) Implication of human endogenous retrovirus envelope proteins in placental functions. Viruses 6:4609–4627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu Q, Li J, Senkowski C, Tang Z, Wang J, Huang T, Wang X, Terry K, Brower S, Glasgow W, Chen H, Jiang SW (2015) Promoter hypermethylation and decreased expression of syncytin-1 in pancreatic adenocarcinomas. PLoS One 10:e0134412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Luo SS, Ishibashi O, Ishikawa G, Ishikawa T, Katayama A, Mishima T, Takizawa T, Shigihara T, Goto T, Izumi A, Ohkuchi A, Matsubara S, Takeshita T, Takizawa T (2009) Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol Reprod 81:717–729

    Article  CAS  PubMed  Google Scholar 

  • Malassine A, Blaise S, Handschuh K, Lalucque H, Dupressoir A, Evain-Brion D, Heidmann T (2007) Expression of the fusogenic HERV-FRD Env glycoprotein (syncytin 2) in human placenta is restricted to villous cytotrophoblastic cells. Placenta 28:185–191

    Article  CAS  PubMed  Google Scholar 

  • Maliniemi P, Vincendeau M, Mayer J, Frank O, Hahtola S, Karenko L, Carlsson E, Mallet F, Seifarth W, Leib-Mosch C, Ranki A (2013) Expression of human endogenous retrovirus-w including syncytin-1 in cutaneous T-cell lymphoma. PLoS One 8:e76281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, Heidmann O, Letzelter C, Richaud A, Ducos B, Heidmann T (2007) Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci U S A 104:20534–20539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteomics 73:1907–1920

    Article  CAS  PubMed  Google Scholar 

  • Matouskova M, Blazkova J, Pajer P, Pavlicek A, Hejnar J (2006) CpG methylation suppresses transcriptional activity of human syncytin-1 in non-placental tissues. Exp Cell Res 312:1011–1020

    Article  CAS  PubMed  Google Scholar 

  • Metz J, Aoki A, Forssmann WG (1978) Studies on the ultrastructure and permeability of the hemotrichorial placenta. I. Intercellular junctions of layer I and tracer administration into the maternal compartment. Cell Tissue Res 192:391–407

    Article  CAS  PubMed  Google Scholar 

  • Mi S, Lee X, Li X, Veldman G, Finnerty H, Racie L, Lavallie E, Tang X, Edouard P, Howes S, Keith J Jr, McCoy J (2000) Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403(6771):785–789

    Article  CAS  PubMed  Google Scholar 

  • Mincheva-Nilsson L, Baranov V (2010) The role of placental exosomes in reproduction. Am J Reprod Immunol 63:520–533

    Article  CAS  PubMed  Google Scholar 

  • Mitchell MD, Peiris HN, Kobayashi M, Koh YQ, Duncombe G, Illanes SE, Rice GE, Salomon C (2015) Placental exosomes in normal and complicated pregnancy. Am J Obstet Gynecol 213:S173–S181

    Article  CAS  PubMed  Google Scholar 

  • Mo H, Ouyang D, Xu L, Gao Q, He X (2013) Human endogenous retroviral syncytin exerts inhibitory effect on invasive phenotype of B16F10 melanoma cells. Chin J Cancer Res 25:556–564

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mohr M, Zaenker KS, Dittmar T (2015) Fusion in cancer: an explanatory model for aneuploidy, metastasis formation, and drug resistance. Methods Mol Biol 1313:21–40

    Article  PubMed  Google Scholar 

  • Munoz-Suano A, Hamilton AB, Betz AG (2011) Gimme shelter: the immune system during pregnancy. Immunol Rev 241:20–38

    Article  CAS  PubMed  Google Scholar 

  • Muyan M, Boime I (1997) Secretion of chorionic gonadotropin from human trophoblasts. Placenta 18:237–241

    Article  CAS  PubMed  Google Scholar 

  • Peleg D, Kennedy CM, Hunter SK (1998) Intrauterine growth restriction: identification and management. Am Fam Physician 58(453–60):466–467

    Google Scholar 

  • Prudhomme S, Oriol G, Mallet F (2004) A retroviral promoter and a cellular enhancer define a bipartite element which controls env ERVWE1 placental expression. J Virol 78:12157–12168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raghupathy R (2013) Cytokines as key players in the pathophysiology of preeclampsia. Med Princ Pract 22(Suppl 1):8–19

    Article  PubMed  Google Scholar 

  • Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172

    Article  CAS  PubMed  Google Scholar 

  • Redelsperger F, Cornelis G, Vernochet C, Tennant BC, Catzeflis F, Mulot B, Heidmann O, Heidmann T, Dupressoir A (2014) Capture of syncytin-Mar1, a fusogenic endogenous retroviral envelope gene involved in placentation in the Rodentia squirrel-related clade. J Virol 88:7915–7928

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Renard M, Varela PF, Letzelter C, Duquerroy S, Rey FA, Heidmann T (2005) Crystal structure of a pivotal domain of human syncytin-2, a 40 million years old endogenous retrovirus fusogenic envelope gene captured by primates. J Mol Biol 352:1029–1034

    Article  CAS  PubMed  Google Scholar 

  • Ruprecht K, Mayerb J, Sautera M, Roemerc K, Mueller-Lantzscha N (2008) Endogenous retroviruses and cancer. Cell Mol Life Sci 65:3366–3382

    Article  CAS  PubMed  Google Scholar 

  • Sahoo S, Klychko E, Thorne T, Misener S, Schultz KM, Millay M, Ito A, Liu T, Kamide C, Agrawal H, Perlman H, Qin G, Kishore R, Losordo DW (2011) Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res 109:724–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salomon C, Torres MJ, Kobayashi M, Scholz-Romero K, Sobrevia L, Dobierzewska A, Illanes SE, Mitchell MD, Rice GE (2014) A gestational profile of placental exosomes in maternal plasma and their effects on endothelial cell migration. PLoS One 9:e98667

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sibai B, Dekker G, Kupferminc M (2005) Pre-eclampsia. Lancet 365:785–799

    Article  PubMed  Google Scholar 

  • Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L (2013) Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. J Immunol 191:5515–5523

    Article  CAS  PubMed  Google Scholar 

  • Stoye JP (2012) Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat Rev Microbiol 10:395–406

    CAS  PubMed  Google Scholar 

  • Strissel PL, Ruebner M, Thiel F, Wachter D, Ekici AB, Wolf F, Thieme F, Ruprecht K, Beckmann MW, Strick R (2012) Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: emergence of new molecular targets. Oncotarget 3:1204–1219

    Article  PubMed  PubMed Central  Google Scholar 

  • Sun Y, Liu J (2014) Potential of cancer cell-derived exosomes in clinical application: a review of recent research advances. Clin Ther 36:863–872

    Article  PubMed  Google Scholar 

  • Sun Y, Ouyang DY, Pang W, Tu YQ, Li YY, Shen XM, Tam SC, Yang HY, Zheng YT (2010) Expression of syncytin in leukemia and lymphoma cells. Leuk Res 34:1195–1202

    Article  CAS  PubMed  Google Scholar 

  • Tarlinton RE, Meers J, Young PR (2006) Retroviral invasion of the koala genome. Nature 442:79–81

    Article  CAS  PubMed  Google Scholar 

  • Taufield PA, Suthanthiran M, Ales K, Druzin M, Resnick LM, Laragh JH, Stenzel KH, Rubin AL (1983) Maternal-fetal immunity: presence of specific cellular hyporesponsiveness and humoral suppressor activity in normal pregnancy and their absence in preeclampsia. Clin Exp Hypertens B 2:123–131

    Article  CAS  PubMed  Google Scholar 

  • Tolosa JM, Schjenken JE, Clifton VL, Vargas A, Barbeau B, Lowry P, Maiti K, Smith R (2012) The endogenous retroviral envelope protein syncytin-1 inhibits LPS/PHA-stimulated cytokine responses in human blood and is sorted into placental exosomes. Placenta 33:933–941

    Article  CAS  PubMed  Google Scholar 

  • Toufaily C, Vargas A, Lemire M, Lafond J, Rassart E, Barbeau B (2013) MFSD2a, the Syncytin-2 receptor, is important for trophoblast fusion. Placenta 34:85–88

    Article  CAS  PubMed  Google Scholar 

  • Toufaily C, Lokossou AG, Vargas A, Rassart E, Barbeau B (2015) A CRE/AP-1-like motif is essential for induced syncytin-2 expression and fusion in human trophoblast-like model. PLoS One 10:e0121468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Trejbalova K, Blazkova J, Matouskova M, Kucerova D, Pecnova L, Vernerova Z, Heracek J, Hirsch I, Hejnar J (2011) Epigenetic regulation of transcription and splicing of syncytins, fusogenic glycoproteins of retroviral origin. Nucleic Acids Res 39:8728–8739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varela M, Spencer TE, Palmarini M, Arnaud F (2009) Friendly viruses: the special relationship between endogenous retroviruses and their host. Ann N Y Acad Sci 1178:157–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vargas A, Moreau J, Landry S, Lebellego F, Toufaily C, Rassart E, Lafond J, Barbeau B (2009) Syncytin-2 plays an important role in the fusion of human trophoblast cells. J Mol Biol 392:301–318

    Article  CAS  PubMed  Google Scholar 

  • Vargas A, Toufaily C, Lebellego F, Rassart E, Lafond J, Barbeau B (2011) Reduced expression of both syncytin 1 and syncytin 2 correlates with severity of preeclampsia. Reprod Sci 18:1085–1091

    Article  CAS  PubMed  Google Scholar 

  • Vargas A, Zhou S, Ethier-Chiasson M, Flipo D, Lafond J, Gilbert C, Barbeau B (2014) Syncytin proteins incorporated in placenta exosomes are important for cell uptake and show variation in abundance in serum exosomes from patients with preeclampsia. FASEB J 28:3703–3719

    Article  CAS  PubMed  Google Scholar 

  • Vlkova B, Szemes T, Minarik G, Turna J, Celec P (2010) Circulating free fetal nucleic acids in maternal plasma and preeclampsia. Med Hypotheses 74:1030–1032

    Article  CAS  PubMed  Google Scholar 

  • Voisset C, Blancher A, Perron H, Mandrand B, Mallet F, Paranhos-Baccalà G (1999) Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in humans and other primates. AIDS Res Hum Retroviruses 15:1529–1533

    Article  CAS  PubMed  Google Scholar 

  • Walker JJ (2000) Pre eclampsia. Lancet 356:1260–1265

    Article  CAS  PubMed  Google Scholar 

  • Warning JC, McCracken SA, Morris JM (2011) A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction 141:715–724

    Article  CAS  PubMed  Google Scholar 

  • Weinstein L (1982) Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142:159–167

    CAS  PubMed  Google Scholar 

  • Wich C, Kausler S, Dotsch J, Rascher W, Knerr I (2009) Syncytin-1 and glial cells missing a: hypoxia-induced deregulated gene expression along with disordered cell fusion in primary term human trophoblasts. Gynecol Obstet Invest 68:9–18

    Article  CAS  PubMed  Google Scholar 

  • Yu C, Shen K, Lin M, Chen P, Lin C, Chang GD, Chen H (2002) GCMa regulates the syncytin-mediated trophoblastic fusion. J Biol Chem 277:50062–50068

    Article  CAS  PubMed  Google Scholar 

  • Yu H, Liu T, Zhao Z, Chen Y, Zeng J, Liu S, Zhu F (2014) Mutations in 3′-long terminal repeat of HERV-W family in chromosome 7 upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb. Oncogene 33:3947–3958

    Article  CAS  PubMed  Google Scholar 

  • Zhuang XW, Li J, Brost BC, Xia XY, Chen HB, Wang CX, Jiang SW (2014) Decreased expression and altered methylation of syncytin-1 gene in human placentas associated with preeclampsia. Curr Pharm Des 20:1796–1802

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Benoit Barbeau .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Toudic, C., Elisseeff, X., Lokossou, A.G., Barbeau, B. (2017). Roles of Endogenous Retrovirus-Encoded Syncytins in Human Placentation. In: Cristofari, G. (eds) Human Retrotransposons in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-48344-3_9

Download citation

Publish with us

Policies and ethics