Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene

Abstract

In most mammalian species, a key process of placenta development is the fusion of trophoblast cells into a highly specialized, multinucleated syncytiotrophoblast layer, through which most of the maternofetal exchanges take place. Little is known about this process, despite the recent identification of 2 pairs of envelope genes of retroviral origin, independently acquired by the human (syncytin-1 and syncytin-2) and mouse (syncytin-A and syncytin-B) genomes, specifically expressed in the placenta, and with in vitro cell-cell fusion activity. By generating knockout mice, we show here that homozygous syncytin-A null mouse embryos die in utero between 11.5 and 13.5 days of gestation. Refined cellular and subcellular analyses of the syncytin-A-deficient placentae disclose specific disruption of the architecture of the syncytiotrophoblastcontaining labyrinth, with the trophoblast cells failing to fuse into an interhemal syncytial layer. Lack of syncytin-A-mediated trophoblast cell fusion is associated with cell overexpansion at the expense of fetal blood vessel spaces and with apoptosis, adding to the observed maternofetal interface structural defects to provoke decreased vascularization, inhibition of placental transport, and fetal growth retardation, ultimately resulting in death of the embryo. These results demonstrate that syncytin-A is essential for trophoblast cell differentiation and syncytiotrophoblast morphogenesis during placenta development, and they provide evidence that genes captured from ancestral retroviruses have been pivotal in the acquisition of new, important functions in mammalian evolution.cell-cell fusion ͉ placenta ͉ syncytiotrophoblast ͉ embryonic lethality ͉ mammalian evolution T he placenta is an autonomous and transient organ of embryonic origin (same genotype as the embryo), essentially intended for feeding and oxygenating the fetus during intrauterine life. In several mammalian species with a hemochorial placenta, including the human and mouse, the fusion of trophoblast cells into a multinucleated layer called the syncytiotrophoblast constitutes a key process of placental morphogenesis (1-4). The syncytiotrophoblast is the main fetomaternal barrier in direct contact with the maternal blood, mediating the essential trophic exchange functions between the mother and the fetus, along with hormone production and protection of the fetus against the mother's immune system. Remarkably, syncytiotrophoblasts are found in the placenta of diverse species belonging to all 4 eutherian superorders, consistent with a convergent evolution process and the presence of strong selective pressures that favor this structure (5, 6). Yet, the molecular mechanisms underlying the convergent emergence of the syncytiotrophoblast remain speculative. Vertebrate genomes harbor thousands of endogenous retrovirus (ERV) elements that display a structure close to that of the integrated proviral form of exogenous retroviruses (gag-, pol-, and env-related regions flanked by 2 LTRs) and that most probably are the remnants of p...

Paleovirology of ‘ syncytins ’, retroviral env genes exapted for a role in placentation

“…As was the case for human syncytin-1, syncytin-B expression is controlled by the Gcm1 transcription factor, in agreement with the fact that the syncytin-B and Gcm1 genes are both expressed in the ST-II layer. Knocking out the syncytin-A gene in mice had dramatic effects, since homozygous mutant embryos died at mid-gestation [54], displaying disruption of the early placental architecture, accumulation of unfused cytotrophoblasts and defective cell-cell fusion within the ST-I layer (figure 4). By contrast, invalidation of the syncytin-B gene had only mild effects, since syncytin-B null embryos were viable, showing only limited late-onset growth retardation and a slight decrease in the number of neonates [55].…”

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

“…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 placenta displayed defects in cell-cell fusion, resulting in decreased maternal-fetal exchanges and impaired embryo survival. Interestingly, other captured env genes have been reported to be expressed specifically in the placenta [e.g., syncytin-like env-Cav1 (14), bosenv4/fematrin-1 (10,15), and enJSRV env (16) genes], with the last one reported to be involved in peri-implantation placental morphogenesis (17).…”

Les syncytines

“…De manière remarquable, le séquençage complet du génome murin a révélé deux gènes d'enveloppes rétrovirales, nommés syncytine-A et -B, distincts des syncytines humaines mais partageant leurs caractéristiques [29] : ils sont exprimés dans le placenta, ont des propriétés fusiogènes, et sont conservés depuis leur intégration chez l'ancêtre des Muridae (rat, souris, hamster, campagnol et gerbille) il y a plus de 25 Ma. L'invalidation du gène codant la syncytine-A chez la souris a des conséquences radicales puisque les embryons homozygotes pour la délétion meurent in utero à mi-gestation [30]. L'architecture placentaire de ces embryons est perturbée, avec une accumulation de trophoblastes non fusionnés, et un défaut de fusion d'une des deux couches distincts, permettrait l'incorporation, par fusion, des cytotrophoblastes mononucléés dans le syncytiotrophoblaste adjacent, tout en évitant que les cytotrophoblastes ne fusionnent entre eux.…”