Fematrin-1 Is Involved in Fetomaternal Cell-to-Cell Fusion in Bovinae Placenta and Has Contributed to Diversity of Ruminant Placentation

Abstract

d During placentation, mammals employ different strategies for nourishing and supporting fetuses. Members of the Bovidae family, consisting of cloven-hoofed ruminants, utilize multiple maternal attachment points on the placenta, known as cotyledons, and hybrid cells, named trinucleate cells or syncytial plaques, made up of a fusion of fetal trophoblasts and maternal endometrial cells to provide essential hormones and maintain long gestation periods. These hybrid cells are unique to the Bovidae, as fetomaternal borders are clearly separated by syncytiotrophoblasts or epithelial cells in the placenta of other mammals. Recently, it was reported that Syncytin-Rum1 was inserted into ruminant genomes, including cattle and sheep, and was possibly involved in fetomaternal cell-to-cell fusion in both species. However, Syncytin-Rum1 alone is insufficient to explain the morphological diversity of the fetomaternal hybrids between Bovinae and Caprinae (i.e., trinucleate cells in Bovinae and syncytial plaques in Caprinae). Here we report that the bovine endogenous retrovirus K1 (BERV-K1) envelope, which we term Fematrin-1, was specifically expressed in binucleated trophoblasts throughout gestation in cattle and induced fusion with bovine endometrial cells in vitro at a significantly higher level than Syncytin-Rum1 under physiological conditions. Fematrin-1 was found to be integrated into intron 18 of FAT tumor suppressor homolog 2 (FAT2) about 18.3 to 25.4 million years ago and has been subject to purifying selection through the evolution of Bovinae. Phylogenetically, Fematrin-1 is distinct from Syncytin genes found in other mammalian species that form syncytiotrophoblasts. Our results suggest that the newly acquired endogenous retroelement has contributed to generating placentation diversity through ruminant evolution.

Continuous model of conceptus implantation to the maternal endometrium

“…However, bovine TE cells form binucleate cells (BNCs) as well as trinucleate cells (TNCs) (Wooding & Beckers 1987). Although it has not been definitively determined whether BNCs result from cell fusion or endoreduplication, it is generally accepted, with exception of the new evidence by Seo and coworkers (Seo et al 2016), that TNCs are products of heterotypic cell fusion between BNCs and uterine epithelial cells (Wooding & Beckers 1987, Dunlap et al 2006, Baba et al 2011, Nakaya et al 2013 and are only localized in the endometrium (Wooding 1992).…”

“…Nevertheless, available data indicate that bovine BNCs undergo a limited invasion, enabling the formation of TNCs with uterine epithelial cells, which are localized in the uterine endometrium (Wooding & Beckers 1987, Lavialle et al 2013, Nakaya et al 2013. It is possible that the formation of TNCs through heterotypic cell fusion may strengthen the adhesion between fetal and maternal tissues in the non-invasive mode of implantation in ruminants.…”

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).…”

Capture of syncytin-Mar1, a Fusogenic Endogenous Retroviral Envelope Gene Involved in Placentation in the Rodentia Squirrel-Related Clade

“…The direct involvement of syncytin genes in placentation has been recently demonstrated unambiguously through the generation of knockout mice for syncytin-A and -B (13,14), whose embryonic placenta displayed defects in cell-cell fusion, resulting in decreased fetomaternal exchange and impaired embryo survival. Interestingly, other captured env genes have been reported to be specifically expressed in the placenta (e.g., syncytin-like env-Cav1 [15], bos-env4/fematrin-1 [11,16], and enJSRV env [1] genes) and for the latter to be involved in peri-implantation placental morphogenesis (17). Therefore, it appears that on several occasions in the course of mammalian evolution, env genes from endogenous retroviruses have been "coopted" by their host to participate in the formation of the placenta.…”