Recently, we and others have identified two human endogenous retroviruses that entered the primate lineage 25-40 million years ago and that encode highly fusogenic retroviral envelope proteins (syncytin-1 and -2), possibly involved in the formation of the placenta syncytiotrophoblast layer generated by trophoblast cell fusion at the materno-fetal interface. A systematic in silico search throughout mouse genome databases presently identifies two fully coding envelope genes, present as unique copies and unrelated to any known murine endogenous retrovirus, that we named syncytin-A and -B. Quantitative RT-PCR demonstrates placentaspecific expression for both genes, with increasing transcript levels in this organ from 9.5 to 14.5 days postcoitum. In situ hybridization of placenta cryosections further localizes these transcripts in the syncytiotrophoblast-containing labyrinthine zona. Consistently, we show that both genes can trigger cell-cell fusion in ex vivo transfection assays, with distinct cell type specificities suggesting different receptor usage. Genes orthologous to syncytin-A and -B and disclosing a striking conservation of their coding status are found in all Muridae tested (mouse, rat, gerbil, vole, and hamster), dating their entry into the rodent lineage Ϸ20 million years ago. Together, these data strongly argue for a critical role of syncytin-A and -B in murine syncytiotrophoblast formation, thus unraveling a rather unique situation where two pairs of endogenous retroviruses, independently acquired by the primate and rodent lineages, would have been positively selected for a convergent physiological role.endogenous retrovirus ͉ placenta ͉ syncytiotrophoblast ͉ rodent E ndogenous retroviruses (ERVs) are present in the genome of all vertebrates (1-3). They are most probably the genomic traces of germ-line infections by exogenous retroviruses having taken place during evolution. Over time, increase in their copy number has occurred, at least for some of them, via retrotransposition or germ-cell reinfection. This generated multigenic families containing a few to several hundred elements and now accounting for a substantial fraction of the genome [8% for the human (4) and 10% for the murine (5) genomes]. In mice, eight families of ERVs, with a structure close to the integrated proviral form of exogenous retroviruses (gag-, pol-, and env-related regions bordered by two LTRs), have been described. Those with close exogenous relatives include type B proviruses related to the murine mammary tumor virus (6) and type C proviruses related to the Moloney murine leukemia virus (MLV), with the endogenous MLV, MuRRS, MuRVY, GLN, MuERVC, and MmERV family members (1,7,8). A family of sequences with no exogenous relatives, called IAPE (intracisternal A-particle sequences with an envelope gene), was also described (9). Although some of these ERVs have accumulated mutations, deletions, and͞or truncations and would therefore require recombination with exogenous counterparts to generate replication-competent retroviruses, oth...