Retroviral envelope syncytin capture in an ancestrally diverged mammalian clade for placentation in the primitive Afrotherian tenrecs

Abstract

Syncytins are fusogenic envelope (env) genes of retroviral origin that have been captured for a function in placentation. Syncytins have been identified in Euarchontoglires (primates, rodents, Leporidae) and Laurasiatheria (Carnivora, ruminants) placental mammals. Here, we searched for similar genes in species that retained characteristic features of primitive mammals, namely the Malagasy and mainland African Tenrecidae. They belong to the superorder Afrotheria, an early lineage that diverged from Euarchotonglires and Laurasiatheria 100 Mya, during the Cretaceous terrestrial revolution. An in silico search for env genes with full coding capacity within a Tenrecidae genome identified several candidates, with one displaying placenta-specific expression as revealed by RT-PCR analysis of a large panel of Setifer setosus tissues. Cloning of this endogenous retroviral env gene demonstrated fusogenicity in an ex vivo cell-cell fusion assay on a panel of mammalian cells. Refined analysis of placental architecture and ultrastructure combined with in situ hybridization demonstrated specific expression of the gene in multinucleate cellular masses and layers at the materno-fetal interface, consistent with a role in syncytium formation. This gene, which we named "syncytin-Ten1," is conserved among Tenrecidae, with evidence of purifying selection and conservation of fusogenic activity. To our knowledge, it is the first syncytin identified to date within the ancestrally diverged Afrotheria superorder.endogenous retrovirus | envelope protein | syncytiotrophoblast | feto-maternal interface | placenta evolution T he syncytins are genes of retroviral origin that have been co-opted by their host for a function in placentation. They correspond to the envelope (env) gene of ancestral retroviruses that entered the germ line of evolutionarily distant animals and were endogenized (reviewed in refs. 1 and 2). Two such genes, syncytin-1 (3, 4) and syncytin-2 (5, 6), have been identified in simians, and distinct, unrelated ones, syncytin-A and -B (7), have been identified in muroid rodents, syncytin-Ory1 (8) in leporids, syncytin-Car1 (9) in carnivorans, and more recently, syncytinRum1 (10) in ruminants. Their canonical characteristic features leading to their designation as "syncytins" comprise (i) placentaspecific expression, (ii) cell-cell fusion activity, and (iii) conservation during the evolution of mammalian species for extended periods of time (e.g., >10 million years). Syncytin proteins are expected to participate in the formation of the placental syncytiotrophoblast (ST) at the maternal-fetal interface via fusion of the mononucleate cytotrophoblasts (CTs). Some of them also possess an immunosuppressive activity, as classically observed for infectious retroviral envelope glycoproteins, which may be involved in maternal-fetal tolerance (11). Recently, the direct involvement of syncytins in placentation has been demonstrated unambiguously through the generation of knockout mice for syncytin-A and -B (12, 13), whose embryonic placent...

Transposable Element Domestication As an Adaptation to Evolutionary Conflicts

“…Syncytins are proteins derived from the Env gene of retroviruses that have been coopted at least nine times during mammal evolution and are thought to play a role in placentation [68-71]. The placenta is a temporary organ that is formed by the fusion of fetal extraembryonic membrane and the maternal uterine tissue, which facilitates metabolic exchanges through the interface between the mother and the fetus [69].…”

“…Knockout studies of two murine-specific Syncytins in the mouse firmly established their critical function in placenta development [72, 73], but it remains unknown whether all Syncytins identified in other mammalian lineages are equally important for placentation. In fact, the evolution of Syncytins presents an evolutionary conundrum, because none are conserved across mammals, but instead each has emerged independently during mammal evolution through cooption events of distinct, lineage-specific retroviral Env sequences [68-71]. Some species like mouse and human even harbor multiple Syncytins in their genomes that originated at different evolutionary time points and there is also evidence that some Syncytins have been lost during evolution [68].…”

Genetic Evidence That Captured Retroviral Envelope syncytins Contribute to Myoblast Fusion and Muscle Sexual Dimorphism in Mice

“…These genes encode fusogenic proteins that are involved in the formation by cell-cell fusion of the placental syncytiotrophoblast in eutherian mammals and marsupials [2–5]. Furthermore, genetically modified mice, knocked out for their two syncytin genes–i.e.…”

Genome-Wide Screening of Retroviral Envelope Genes in the Nine-Banded Armadillo (Dasypus novemcinctus, Xenarthra) Reveals an Unfixed Chimeric Endogenous Betaretrovirus Using the ASCT2 Receptor

“…A BLAST search identified 162 putative retroviral env genes. This number far exceeds those found in the genomes of other mammalian species for which we performed a strictly similar screening (i.e., 9 in Echinops telfairi [40] and 18 in Bos taurus [51]). This is consistent with data from a previous study by Hayward et al (10), who screened vertebrate genomes for the presence of high-quality ERVs containing conserved gag and pol motifs and reported a higher number of ERVs in the genome of the ninebanded armadillo than in the genomes of many other mammals (10).…”

“…To identify putative env-derived genes in the nine-banded armadillo genome sequence (6ϫ coverage assembly of the Dasypus novemcinctus genome; NCBI, Dasnov3.0, January 2012), we made use of a method that we previously devised to screen the tenrec genome for such genes (40). Basically, a BLAST search for ORFs (from the Met start codon to the stop codon) of Ͼ400 amino acids (aa) was performed by using a selected series of Env protein sequences, including all presently identified syncytins (see Materials and Methods).…”