Capture of syncytin-Mar1, a fusogenic endogenous retroviral envelope gene involved in placentation in the Rodentia squirrel-related clade.
Syncytin genes are fusogenic envelope protein (env) genes of retroviral origin that have been captured for a function in placentation. Within rodents, two such genes have previously been identified in the mouse-related clade, allowing a demonstration of their essential role via knockout mice. Here, we searched for similar genes in a second major clade of the Rodentia order, the squirrel-related clade, taking advantage of the complete sequencing of the ground squirrel Ictidomys tridecemlineatus genome. In silico search for env genes with full coding capacity identified several candidate genes with one displaying placenta-specific expression, as revealed by quantitative reverse transcription-PCR analysis of a large panel of tissues. This gene belongs to a degenerate endogenous retroviral element, with recognizable hallmarks of an integrated provirus. Cloning of the gene in an expression vector for ex vivo cell-cell fusion and pseudotype assays demonstrated fusogenicity on a large panel of mammalian cells. In situ hybridization on placenta sections showed specific expression in domains where trophoblast cells fuse into a syncytiotrophoblast at the fetomaternal interface, consistent with a role in syncytium formation. Finally, we show that the gene is conserved among the tribe Marmotini, thus dating its capture back to about at least 25 million years ago, with evidence for purifying selection and conservation of fusogenic activity. This gene that we named syncytin-Mar1 is distinct from all seven Syncytin genes identified to date in eutherian mammals and is likely to be a major effector of placentation in its related clade. Importance: Syncytin genes are fusogenic envelope genes of retroviral origin, ancestrally captured for a function in placentation. Within rodents, two such genes had been previously identified in the mouse-related clade. Here, in the squirrel-related rodent clade, we identified the envelope gene of an endogenous retrovirus with all the features of a Syncytin: it is specifically expressed in the placenta of the woodchuck Marmota monax, at the level of cells fusing into a syncytium; it can trigger cell-cell and virus-cell fusion ex vivo; and it has been conserved for >25 million years of evolution, suggesting an essential role in its host physiology. Remarkably, syncytin-Mar1 is unrelated to all other Syncytin genes identified thus far in mammals (primates, muroids, carnivores, and ruminants). These results extend the range of retroviral envelope gene "domestication" in mammals and show that these events occurred independently, on multiple occasions during evolution to improve placental development in a process of convergent evolution.
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, CNRS UMR 8122, Institut Gustave Roussy, Villejuif, France Université Paris-Sud, Orsay, France.
François
F
Redelsperger
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, CNRS UMR 8122, Institut Gustave Roussy, Villejuif, France Université Paris-Sud, Orsay, France Université Paris Denis Diderot, Sorbonne Paris-Cité, Paris, France.
Guillaume
G
Cornelis
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, CNRS UMR 8122, Institut Gustave Roussy, Villejuif, France Université Paris-Sud, Orsay, France.
Cécile
C
Vernochet
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Bud C
BC
Tennant
Laboratoire de Paléontologie, Phylogénie et Paléobiologie, UMR 5554 CNRS, Université Montpellier II, Montpellier, France.
François
F
Catzeflis
ZooParc de Beauval et Beauval Nature, Saint Aignan, France.
Baptiste
B
Mulot
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, CNRS UMR 8122, Institut Gustave Roussy, Villejuif, France Université Paris-Sud, Orsay, France.
Odile
O
Heidmann
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, CNRS UMR 8122, Institut Gustave Roussy, Villejuif, France Université Paris-Sud, Orsay, France heidmann@igr.fr.
Thierry
T
Heidmann
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, CNRS UMR 8122, Institut Gustave Roussy, Villejuif, France Université Paris-Sud, Orsay, France.
Anne
A
Dupressoir
D000818:Animals; D017124:Conserved Sequence; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015686:Gene Products, env / Q000096:biosynthesis / Q000235:genetics*; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D010929:Placentation; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012589:Sciuridae / Q000235:genetics / Q000502:physiology* / Q000821:virology*; D017422:Sequence Analysis, DNA
D015686:Gene Products, env; D011257:Pregnancy Proteins; C405335:syncytin