During their replication, infectious retroviruses insert a reverse-transcribed cDNA copy of their genome, a "provirus", into the genome of their host. If the infected cell belongs to the germline, the integrated provirus can become "fixed" within the host genome as an endogenous retrovirus and be transmitted vertically to the progeny in a Mendelian fashion. Based on the numerous proviral sequences that are recovered within the genomic DNA of vertebrates--up to ten percent in the case of mammals--such events must have occurred repeatedly during the course of millions of years of evolution. Although most of the ancient proviral sequences have been disrupted, a few "endogenized" retroviral genes are conserved and still encode functional proteins. In this review, we focus on the recent discovery of genes derived from the envelope glycoprotein-encoding (env) genes of endogenous retroviruses that have been domesticated by mammals to carry out an essential function in placental development. They were called syncytins based on the membrane fusogenic capacity that they have kept from their parental env gene and which contributes to the formation of the placental fused cell layer called the syncytiotrophoblast, at the materno-fetal interface. Remarkably, the capture of syncytin or syncytin-like genes, sometimes as pairs, was found to have occurred independently from different endogenous retroviruses in diverse mammalian lineages such as primates--including humans--, muroids, leporids, carnivores, caviids, and ovis, between around 10 and 85 million years ago. Knocking out one or both mouse syncytin-A and -B genes provided evidence that they indeed play a critical role in placentation. We discuss the possibility that the immunosuppressive domain embedded within retroviral envelope glycoproteins and conserved in syncytin proteins, may be involved in the tolerance of the fetus by the maternal immune system. Finally, we speculate that the capture of a founding syncytin-like gene could have been instrumental in the dramatic transition from egg-laying to placental mammals.
"It has been hypothesised that maintenance of the encoding ability of endogenous retroviruses may have important roles, e.g., maintenance of physiological functions during reproduction, pathophysiological negative effects in cancer (Prudhomme et al., 2005; Jern and Coffin, 2008) or protection against exogenous retroviruses at the entry level by inducing cellular resistance to exogenous viruses through receptor interference (Ikeda and Sugimura, 1989; Ponferrada et al., 2003) or during retroviral replication (Pryciak and Varmus, 1992). The endogenous Jaagsiekte Sheep RetroViruses are essential for placental development in sheep as shown for independently acquired endogenous retroviruses in humans or rodents (Taruscio and Mantovani, 2004; Prudhomme et al., 2005; Dunlap et al., 2006; Dupressoir et al., 2012; Lavialle et al., 2013). A role, if any, of them in cancer development is not clearly identified. "
[Show abstract][Hide abstract] ABSTRACT: Sheep and goats are widely infected by oncogenic retroviruses, namely Jaagsiekte Sheep RetroVirus (JSRV) and Enzootic Nasal Tumour Virus (ENTV). Under field conditions, these viruses induce transformation of differentiated epithelial cells in the lungs for Jaagsiekte Sheep RetroVirus or the nasal cavities for Enzootic Nasal Tumour Virus. As in other vertebrates, a family of endogenous retroviruses named endogenous Jaagsiekte Sheep RetroVirus (enJSRV) and closely related to exogenous Jaagsiekte Sheep RetroVirus is present in domestic and wild small ruminants. Interestingly, Jaagsiekte Sheep RetroVirus and Enzootic Nasal Tumour Virus are able to promote cell transformation, leading to cancer through their envelope glycoproteins. In vitro, it has been demonstrated that the envelope is able to deregulate some of the important signaling pathways that control cell proliferation. The role of the retroviral envelope in cell transformation has attracted considerable attention in the past years, but it appears to be highly dependent of the nature and origin of the cells used. Aside from its health impact in animals, it has been reported for many years that the Jaagsiekte Sheep RetroVirus-induced lung cancer is analogous to a rare, peculiar form of lung adenocarcinoma in humans, namely lepidic pulmonary adenocarcinoma. The implication of a retrovirus related to Jaagsiekte Sheep RetroVirus is still controversial and under investigation, but the identification of an infectious agent associated with the development of lepidic pulmonary adenocarcinomas might help us to understand cancer development. This review explores the mechanisms of induction of respiratory cancers in small ruminants and the possible link between retrovirus and lepidic pulmonary adenocarcinomas in humans.
"A good documented evolutionary example would be the Kat1 gene of the yeast Kluyveromyces, which participates in mating type switching and is derived from a transposition event at the base of this genus (Rajaei et al. 2014). In mammalian evolution, envelope genes of ERVs have been converted to syncytin genes (essential for placenta formation) multiple times (Dupressoir et al. 2012). And quite spectacularly, Drosophila telomeres are believed to be maintained by repurposed non-LTR retrotransposon reverse transcriptases (Belfort et al. 2011). "
"Our careful observation by the electron microscopy revealed that the cell fusion of ST-II was incomplete in the Vash2(−/−) mice (Fig. 5B). Murine endogenous retrovirus (ERV) envelope glycoprotein syncytin-A (Syn-A) and syncytin-B (Syn-B) are expressed in trophoblasts and regulates their fusion , . The transcription factor glial cells missing-1 (Gcm-1) regulates the expression of Syn-A . "
[Show abstract][Hide abstract] ABSTRACT: Vasohibin-1 (VASH1) and vasohibin-2 (VASH2), the 2 members of the vasohibin family, have been identified as novel regulators of angiogenesis. VASH1 ceases angiogenesis, whereas VASH2 stimulates sprouting. Here we characterized their functional role in the placenta. Immunohistochemical analysis of human placental tissue clarified their distinctive localization; VASH1 in endothelial cells and VASH2 in trophoblasts. We then used a mouse model to explore their function. Wild-type, Vash1(-/-), and Vash2(-/-) mice on a C57BL6 background were used in their first pregnancy. As expected, the fetal vascular area was increased in the Vash1(-/-) mice, whereas it was decreased in the Vash2(-/-) mice relative to wild-type. In addition, we noticed that the Vash2(-/-) mice at 18.5dpc displayed thinner villi of the labyrinth and larger maternal lacunae. Careful observation by an electron microscopy revealed that the syncytiotrophoblast formation was defective in the Vash2(-/-) mice. To test the possible involvement of VASH2 in the syncytiotrophoblast formation, we examined the fusion of BeWo cells, a human trophoblastoid choriocarcinoma cell line. The forskolin treatment induced the fusion of BeWo cells, and the knockdown of VASH2 expression significantly inhibited this cell fusion. Conversely, the overexpression of VASH2 by the infection with adenovirus vector encoding human VASH2 gene significantly increased the fusion of BeWo cells. Glial cell missing-1 and endogenous retrovirus envelope glycoprotein Syncytin 1 and Syncytin 2 are known to be involved in the fusion of trophoblasts. However, VASH2 did not alter their expression in BeWo cells. These results indicate that VASH1 and VASH2 showed distinctive localization and opposing function on the fetoplacental vascularization. Moreover, our study shows for the first time that VASH2 expressed in trophoblasts is involved in the regulation of cell fusion for syncytiotrophoblast formation.
PLoS ONE 09/2014; 9(9):e104728. DOI:10.1371/journal.pone.0104728 · 3.23 Impact Factor
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