From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation.
ABSTRACT 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.
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ABSTRACT: We here review the evolution of invasive placentation in primates towards the deep penetration of the endometrium and its arteries in hominoids. The strepsirrhine primates (lemurs and lorises) have non-invasive, epitheliochorial placentation, although this is thought to be derived from a more invasive type. In haplorhine primates, there is differentiation of trophoblast at the blastocyst stage into syncytial and cellular trophoblast. Implantation involves syncytiotrophoblast that first removes the uterine epithelium then consolidates at the basal lamina before continuing into the stroma. In later stages of pregnancy, especially in Old World monkeys and apes, cytotrophoblast plays a greater role in the invasive process. Columns of trophoblast cells advance to the base of the implantation site where they spread out to form a cytotrophoblastic shell. In addition, cytotrophoblasts advance into the lumen of the spiral arteries. They are responsible for remodelling these vessels to form wide, low-resistance conduits. In human and great apes, there is additional invasion of the endometrium and its vessels by trophoblasts originating from the base of the anchoring villi. Deep trophoblast invasion that extends remodelling of the spiral arteries to segments in the inner myometrium evolved in the common ancestor of gorilla, chimp and human. © 2015 The Author(s) Published by the Royal Society. All rights reserved.Philosophical Transactions of The Royal Society B Biological Sciences 03/2015; 370(1663). DOI:10.1098/rstb.2014.0070 · 6.31 Impact Factor
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ABSTRACT: Syncytins are genes of retroviral origin captured by eutherian mammals, with a role in placentation. Here we show that some marsupials-which are the closest living relatives to eutherian mammals, although they diverged from the latter ∼190 Mya-also possess a syncytin gene. The gene identified in the South American marsupial opossum and dubbed syncytin-Opo1 has all of the characteristic features of a bona fide syncytin gene: It is fusogenic in an ex vivo cell-cell fusion assay; it is specifically expressed in the short-lived placenta at the level of the syncytial feto-maternal interface; and it is conserved in a functional state in a series of Monodelphis species. We further identify a nonfusogenic retroviral envelope gene that has been conserved for >80 My of evolution among all marsupials (including the opossum and the Australian tammar wallaby), with evidence for purifying selection and conservation of a canonical immunosuppressive domain, but with only limited expression in the placenta. This unusual captured gene, together with a third class of envelope genes from recently endogenized retroviruses-displaying strong expression in the uterine glands where retroviral particles can be detected-plausibly correspond to the different evolutionary statuses of a captured retroviral envelope gene, with only syncytin-Opo1 being the present-day bona fide syncytin active in the opossum and related species. This study would accordingly recapitulate the natural history of syncytin exaptation and evolution in a single species, and definitely extends the presence of such genes to all major placental mammalian clades.Proceedings of the National Academy of Sciences 01/2015; 112(5). DOI:10.1073/pnas.1417000112 · 9.81 Impact Factor
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ABSTRACT: Human endogenous retroviruses of the HERV-K(HML-2) group have been associated with the development of tumor diseases. Various HERV-K(HML-2) loci encode retrovirus-like proteins, and expression of such proteins is upregulated in certain tumor types. HERV-K(HML-2)-encoded Rec and Np9 proteins interact with functionally important cellular proteins and may contribute to tumor development. Though, the biological role of HERV-K(HML-2) transcription and encoded proteins in health and disease is less understood. We therefore investigated transcription specifically of HERV-K(HML-2) rec and np9 mRNAs in a panel of normal human tissues. We obtained evidence for rec and np9 mRNA being present in all examined 16 normal tissue types. A total of 18 different HERV-K(HML-2) loci were identified as generating rec or np9 mRNA, among them loci not present in the human reference genome and several of the loci harboring open reading frames for Rec or Np9 proteins. Our analysis identified additional alternative splicing events of HERV-K(HML-2) transcripts, some of them encoding variant Rec/Np9 proteins. We also identified a second HERV-K(HML-2) locus formed by L1-mediated retrotransposition that is likewise transcribed in various human tissues. HERV-K(HML-2) rec and np9 transcripts from different HERV-K(HML-2) loci appear to be present in various normal human tissues. It is conceivable that Rec and Np9 proteins and variants of those proteins are part of the proteome of normal human tissues and thus various cell types. Transcription of HERV-K(HML-2) may thus also have functional relevance in normal human cell physiology.