Endogenous retroviruses regulate periimplantation placental growth and differentiation

Abstract

Endogenous retroviruses (ERVs) are fixed and abundant in the genomes of vertebrates. Circumstantial evidence suggests that ERVs play a role in mammalian reproduction, particularly placental morphogenesis, because intact ERV envelope genes were found to be expressed in the syncytiotrophoblasts of human and mouse placenta and to elicit fusion of cells in vitro. We report here in vivo and in vitro experiments finding that the envelope of a particular class of ERVs of sheep, endogenous Jaagsiekte sheep retroviruses (enJSRVs), regulates trophectoderm growth and differentiation in the periimplantation conceptus (embryo͞fetus and associated extraembryonic membranes). The enJSRV envelope gene is expressed in the trophectoderm of the elongating ovine conceptus after day 12 of pregnancy. Loss-of-function experiments were conducted in utero by injecting morpholino antisense oligonucleotides on day 8 of pregnancy that blocked enJSRV envelope protein production in the conceptus trophectoderm. This approach retarded trophectoderm outgrowth during conceptus elongation and inhibited trophoblast giant binucleate cell differentiation as observed on day 16. Pregnancy loss was observed by day 20 in sheep receiving morpholino antisense oligonucleotides. In vitro inhibition of the enJSRV envelope reduced the proliferation of mononuclear trophectoderm cells isolated from day 15 conceptuses. Consequently, these results demonstrate that the enJSRV envelope regulates trophectoderm growth and differentiation in the periimplantation ovine conceptus. This work supports the hypothesis that ERVs play fundamental roles in placental morphogenesis and mammalian reproduction.development ͉ placenta ͉ sheep ͉ trophectoderm T he sheep genome contains Ϸ20 copies of endogenous retroviruses (ERVs) highly related to the exogenous and pathogenic Jaagsiekte sheep retrovirus (JSRV) (1-3). Endogenous JSRVs (enJSRVs) are abundantly expressed in the epithelia of the female genital tract (4). In the placenta, enJSRVs are expressed in the mononuclear trophectoderm cells of the conceptus (embryo͞fetus and associated extraembryonic membranes) and are most abundant in the trophoblast giant binucleate cells (BNCs) and multinucleated syncytial plaques of the placentomes (5-7). The temporal expression of the enJSRV envelope (env) gene in the trophectoderm is coincident with key events in the development of the sheep conceptus (8). enJSRV env mRNAs are first detected at day 12 (5), when the blastocyst begins the process of elongation, involving the intense proliferation and outgrowth of mononuclear trophectoderm cells producing IFN-, the antiluteolytic signal for pregnancy recognition in ruminants (9, 10).In sheep, trophoblast giant BNCs differentiate from mononuclear trophectoderm cells beginning on day 14, migrate, and then fuse with the uterine luminal epithelium, as well as each other, to form multinucleated syncytial plaques that ultimately form the cotyledonary portions of the placenta (11). The BNCs derive from the mononuclear trophectoderm cells by a poorly ch...

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

“…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).…”

Transposable elements as drivers of genomic and biological diversity in vertebrates

“…The fusogenic activity of Syncytin-1 is hominoid-specific and conserved in chimpanzee, gorilla, orang-utan and gibbon (Mallet et al 2004). Syncytin-like genes of retroviral origin with potential roles in placenta formation have also been identified in mouse and sheep (Dupressoir et al 2005, Dunlap et al 2006. Interestingly, Syncytin-like genes have been introduced into primate, murine and ovine lineages through independent retroviral infections.…”

Les syncytines

“…Enfin, soulignons que l'importance de la capture de gènes dans la morphogenèse placentaire ne se limite pas aux gènes de syncytines. En effet, chez la brebis, des expériences d'injection in utero d'oligonucléotides antisens ont montré que les gènes d'enveloppe d'une famille d'ERV (enJSRV) sont impliqués dans la différenciation et la régulation de la croissance placentaires lors de l'implantation [33]. De même deux gènes, Peg10 (paternally expressed gene 10) et Rtl1, conservés chez tous les mammifères euthériens et dérivés de l'insertion de rétro-transposons sushi-ichi 2 à LTR (long terminal repeat), contrôlent l'un le développement précoce et l'autre le développement tardif de la placentation (revue dans [34,38]).…”