Human endogenous retrovirus (HERV) sequences make up approximately 8% of the human genome, and are believed to be remnants of retroviral infection that occurred during primate evolution (Antony et al., 2004).

The multiple sclerosis-associated retrovirus (MSRV) is related to HERVs. By screening placental tissue with MSRV and ERV9 probes, followed by RT-PCR, Blond et al. (1999) obtained a cDNA encoding an HERV-tryptophan (HERV-W) envelope protein, ERVWE1. The deduced 538-amino acid envelope protein contains an N-terminal leader peptide and a putative C-terminal hydrophobic membrane-anchoring sequence. A furin cleavage site separates the transmembrane and surface subdomains, which have 1 and 7 potential glycosylation sites, respectively. SDS-PAGE analysis detected expression of a 60-kD envelope protein after in vitro transcription-translation and an 80-kD protein after glycosylation. Northern blot analysis detected 8.0-, 3.1-, and 1.3-kb HERV-W transcripts only in placenta.

Many mammalian viruses have acquired genes from their hosts during their evolution. The rationale for these acquisitions is usually quite clear: the captured genes are subverted to provide a selective advantage to the virus. Mi et al. (2000) described the opposite situation, where a viral gene has been sequestered to serve an important function in the physiology of a mammalian host. This gene, encoding a protein that they called syncytin, is the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W. As part of a project to identify novel secreted proteins, Mi et al. (2000) isolated a cDNA fragment comprising the 5-prime end of the syncytin gene from a human testis library using the yeast signal sequence trap. They subsequently isolated a full-length human syncytin cDNA from the same source. The syncytin gene encodes a protein of 538 amino acids with a 20-amino acid signal sequence. Hydrophobicity analysis suggested that syncytin is a type 1 membrane protein, with its transmembrane region encoded in the carboxy terminus. Many retroviral envelope proteins are reported to mediate immunosuppression through a conserved segment of 25 amino acids located in their extracellular domains. This sequence is also found in syncytin at amino acid residues 373 to 397. Northern blot analysis showed that syncytin expression is limited to placenta, where 2 major transcripts of 4 and 8 kb are expressed at very high levels, and testis, where expression is weaker and the 8-kb transcript predominates. In the placenta, syncytin expression was restricted to syncytiotrophoblasts, multinucleated cells that originate from fetal trophoblasts.

Mi et al. (2000) suggested that abundant syncytin expression in placental syncytiotrophoblasts may contribute towards immune tolerance of the developing embryo. Southern blot analysis identified multiple copies of syncytin-related sequences in the human and rhesus monkey genomes; however, no evidence was found for homologs in any other species tested, including representatives of several other mammalian orders. Expression of recombinant syncytin in a wide variety of cell types induced the formation of giant syncytia, and fusion of a human trophoblastic cell line expressing endogenous syncytin was inhibited by an anti-syncytin antiserum. Trophoblast invasion of the maternal decidua and myometrium is a carefully orchestrated process, with insufficient infiltration of the uterine wall implicated in placental disorders such as preeclampsia, and uncontrolled trophoblast invasion observed in choriocarcinoma and other gestational trophoblastic diseases. Mi et al. (2000) suggested that syncytin may limit invasiveness by inducing trophoblast fusion and terminal differentiation. They concluded that syncytin may mediate placental cytotrophoblast fusion in vivo, and thus may be important in human placental morphogenesis.

Using cell fusion assays, Blond et al. (2000) showed that ERVWE1 encodes a highly fusogenic membrane glycoprotein that can induce syncytium formation upon interaction with the type D mammalian retrovirus receptor. Immunohistochemical analysis showed ERVWE1 expression restricted to placenta, particularly in the cytotrophoblast and with stronger expression in the syncytiotrophoblast cell layer.

Antony et al. (2004) found that syncytin was upregulated 3-fold in astrocytes and glial cells within acute demyelinating lesions of patients with multiple sclerosis (MS; 126200) compared to controls. Using an HERV-W expression vector, the authors found that syncytin induced proinflammatory molecules, including interleukin-1-beta (147720), inducible NOS (see 163731), and other toxic redox reactants that were cytotoxic to myelin-forming oligodendrocytes. In a mouse model of MS, the antioxidant ferulic acid abrogated neuroinflammation, myelin damage, and some neurobehavioral abnormalities.

Using a tumor rejection assay, Mangeney et al. (2007) showed that both human and mouse syncytin-2 (610524) were immunosuppressive, whereas human and mouse syncytin-1 were not. Mutation analysis identified a residue critical for immunosuppressive activity, which was independent of the primary fusogenic activity of these proteins. Mangeney et al. (2007) proposed that immunosuppressive syncytins may be important in fetomaternal tolerance.

By Southern blot and sequence database analyses, Blond et al. (1999) determined that HERV-W is a widely distributed, multicopy gene family, with sequences on chromosomes 7q21-q22, 14q11-q12, 21q22.3, and Xq22.

Based on sequence similarity between the syncytin cDNA (GenBank AF208161) and a syncytin open reading frame within a mapped BAC (GenBank AC000064), Mi et al. (2000) assigned the syncytin gene to human chromosome 7q21-q22.

Dupressoir et al. (2005) found that rodents express 2 endogenous retroviral envelope genes, syncytin A and syncytin B, that are homologous but not orthologous to the human syncytin genes. These genes entered the rodent lineage approximately 20 million years ago and exhibit properties similar to those of the human syncytin genes, including specific expression in placenta.

Caceres et al. (2006) stated that HERV-W is thought to have invaded the primate genome less than 40 million years ago, after the divergence of catarrhines and New World monkeys. They found that the syncytin gene is inactive in Old World monkeys. Caceres et al. (2006) determined that the evolution of syncytin in hominoids involved an accumulation of amino acid changes and showed signatures of both positive and purifying selection. They concluded that syncytin is indeed a hominoid-specific gene.

Dupressoir et al. (2009) found that syncytin A +/- mice were viable and fertile and exhibited no obvious phenotype. However, syncytin A -/- embryos died at midgestation, between embryonic days 11.5 and 13.5. Syncytin A -/- embryos showed no gross abnormalities, but they were growth retarded and were paler than wildtype or syncytin A +/- embryos, with decreased vascularization of their extraembryonic annexes and reduced blood vessel branching. Syncytin A -/- placentas were of normal size, and the spongiotrophoblast and giant cell zone appeared normal, but the labyrinth, which is involved in fetomaternal exchange, was abnormally compact, with clusters of densely packed trophoblast cells and apoptotic cells. The abnormal expansion of trophoblast cells appeared to cause secondary compression of fetal blood supply, leading to embryonic death. Dupressoir et al. (2009) concluded that suncytin A is essential for trophoblast cell differentiation and syncytiotrophoblast morphogenesis during placenta development.