By Vivienne Baillie Gerritsen
Does placental evolution finds its origins in the doings of a virus?
Who would have thought that a virus could have anything to do with a tissue as important to life, and its development, as the placenta? A viral protein, now known as syncytin, whose gene was probably integrated into the primate genome over 25 millions years ago, is hugely expressed in placental tissue – especially at the beginning of embryonic development – and is giving signs of bearing an essential role in placental architecture. Could it be then that placental evolution, and indeed mammalian evolution, finds its origins in the doings of a virus?
The virus in question is in fact a retrovirus known as human endogenous retrovirus : HERV-W. The human genome – as indeed many other eukaryotic genomes – is sprinkled with retroviral genes and sports up to 8% of endogenous retroviral sequences! With the passing of time, many of them become dysfunctional due to mutations but a number of them do seem to survive and their sequence can be translated into healthy proteins. It is not always clear how their expression could benefit the host’s biology but the discovery, in the year 2000, of the retroviral protein syncytin may well be a fascinating example of how a retroviral product has been integrated and kept relatively intact throughout time, in the host’s genome, and whose function – possibly via natural selection – serves the host’s purpose.
Syncytin is a 538 amino-acid viral envelope protein, which exhibits a transmembrane and a cytoplasmic subunit. It is thought that these two subunits are posttranslationally cleaved and meet up at the cell’s membrane. In general, a viral envelope protein mediates cell fusion and participates in building up the virus’ envelope. What was discovered was that syncytin seems to fulfill the same purpose in humans, i.e. cell fusion, but at the level of the placenta.
Fig. 1 The foetus in the womb, Leonardo da Vinci (c.1510-1512)
The placenta is lined, on the mother’s side, by a tissue known as the syncytiotrophoblast – from where the protein’s name derives. The syncytiotrophoblast is an essential tissue for the proper development of the embryo, acting as a place of nutritional exchange between the mother and her child, as well as a center for hormone synthesis and what is more, it has a role in the foetus’ immunity. The syncytiotrophoblast is a one-celled layer formed via the fusion of trophoblasts. But what exactly are trophoblasts? Trophoblasts are the cells which accompany the foetus in the very early stages of development giving it all it needs and helping it to anchor itself in the womb. The fusion of trophoblasts creates the syncytiotrophoblast, the tissue which hugs the placenta. And yes, you guessed, syncytin is involved in the fusion of trophoblasts.
In ‘normal’ circumstances, i.e. in the event of viral infection, syncytin would be synthesized thanks to the host’s translating machinery and would then be found at the surface of a viral cell. From there it would recognize a specific receptor on a second viral cell, make a beeline for it, and mediate cell fusion. Syncytin has been squatting the human genome for millions of years now; it still does use our machinery to be expressed but instead of initiating viral envelope formation, it is involved in mediating trophoblast fusion. Indeed, the expression of syncytin during placental formation is high. And what is more, besides some expression in the testis, this seems to be the only place the protein is expressed. « Syncytin has been squatting the human genome for millions of years now. »
Not only does syncytin have a role in placental morphogenesis but it may well have a role in driving off viral infection too. How? Via receptor interference. When syncytin drives trophoblast fusion to form the syncytiotrophoblast, it probably does so by using cell receptors that are used by other ‘healthy’ invading viruses. If syncytin grabs the receptor before another viral envelope protein gets the chance, it is in effect interfering with the formation of invading viruses and hence viral infection of the foetus. Which is good news. A little mind-boggling to realize that a virus is at the heart of something so essential as the human placenta and what is more is capable of fighting off ... viral infection of the human foetus. Here is a virus we owe one to!
Hence, from an evolutionary point of view, syncytin could have quite a role in placental development. So far though, it seems that HERV-W is only shared between humans and higher primates which wouldn’t make much of a basis for a major role in placental evolution. However, interestingly, there are a number of different HERV-W families which are found dispersed in various mammals. Could it be then that various viral families are at the heart of the diverse types of placenta observed in mammals today? Certainly, syncytin does appear to have something to do with certain malfunctions of the placenta such as pre-eclampsia (high blood pressure, weight gain and convulsions) or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome because, in the event of such ailments, it is not expressed at the normal levels.
All this raises hopes in the field of biotechnology and the search for treatments against such diseases during pregnancy – although both diseases are multisystem disorders, and cell fusion is a far more complicated process than the mere recognition of a membrane receptor by syncytin. However, the discovery of specific amino acids within the syncytin sequence, which are paramount in receptor recognition, could provide a basis for the genetic engineering of the syncytin polypeptide. Indeed, it has been shown that the fusogenic protein when expressed in tumor cells can bring about cell fusion and subsequently tumor cell death. The ugly part is that syncytin could even perhaps participate in envelope formation of invading viruses, such as HIV-1 for instance, and potentially contribute to its pathogenesis. Time will tell.
- References
- 1. Frendo J.-L., Olivier D., Cheynet V., Blond J.L., Bouton O., Vidaud M., Rabreau M., Evain-Brion D., Mallet F.Direct involvement of HERV-W env glycoprotein in human trophoblast cell fusion and differentiationMol. Cell Biol. 23:3566-3574(2003)PMID: 12724415.
- 2. Knerr I., Beinder E., Rascher W.Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndromeAm. J. Obstet. Gynecol. 186:210-213(2002)PMID: 11854637.
- 3. 3. Mi S., Lee X., Li X.-P., Veldman G.M., Finnerty H., Racie L., LaVallie E., Tang X.-Y., Edouard P., Howes S., Keith J.C., McCoy J.M.Syncytin is a captive retroviral envelope protein involved in human placental morphogenesisNature 403:785-789(2000)PMID: 10693809.
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