Murine Endogenous Retrovirus MuERV-L Is the Progenitor of the “Orphan” Epsilon Viruslike Particles of the Early Mouse Embryo

Abstract

Viruslike particles which displayed a peculiar wheellike appearance that distinguished them from A-, B-or C-type particles had previously been described in the early mouse embryo. The maximum expression of these so-called epsilon particles was observed in two-cell-stage embryos, followed by their rapid decline at later stages of development and no particles detected at the zygote one-cell stage. Here, we show that these particles are in fact produced by a newly discovered murine endogenous retrovirus (ERV) belonging to the widespread family of mammalian ERV-L elements and named MuERV-L. Using antibodies that we raised against the Gag protein of these elements, Western blot analysis and in toto immunofluorescence studies of the embryos at various stages disclosed the same developmental expression profile as that observed for epsilon particles. Using expression vectors for cloned, full-length, entirely coding MuERV-L copies and cell transfection, direct identification of the epsilon particles was finally achieved by high-resolution electron microscopy.Multiple viruslike particles are generated by mouse tissues under normal and/or pathological conditions. These have been initially characterized according to morphological criteria by electron microscopic examination and classified as type A, B, C, and epsilon particles depending on their site of assembly (i.e., within the cell cytoplasm or at the cell surface) and the structure of the mature particles (3, 24; reviewed in reference 16). These particles were suspected to be generated by socalled endogenous retroviruses (ERVs), as they can be observed in normal animals in the absence of any exogenous infection. Some of these particles were even observed in the developing embryo and, for some of them, at very early stages with, for instance, a peak of occurrence of particles of the epsilon type at the two-cell stage (23,24). In most cases, the ERVs responsible for the formation of these particles have been identified, thanks to the complete sequencing of the mouse genome (15a), the in silico identification of elements with full coding capacity, and, finally, the cloning of functional copies that could be demonstrated to be responsible for the synthesis of the corresponding particles in appropriate ex vivo assays by electron microscopic analysis. Examples include the highly reiterated intracisternal A-type particles (IAPs) (7; reviewed in reference 12), the Mus musculus type D (MusD) intracytoplasmic elements (18,19), and the endogenous murine leukemia virus and mouse mammary tumor virus (reviewed in reference 4). Yet, the epsilon particles, first identified more than 25 years ago in mouse embryos (23, 24) and later in some iododeoxyuridine-induced mouse cell lines (13,14), have up to now remained "orphan." Actually, these particles have a rather unusual morphology, with a wheel-shaped core disclosing an electron-lucent space surrounded by two concentric electron-dense rings that are separated by a radial array of internal spikes, not found in any present-day infectious ...

Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A

“…These include Zscan4, Tcstv1/3, Eif1a (Gm2022), Similar to Tho4, and Zfp352 (Kigami et al 2003;Liu et al 2003;Svoboda et al 2004;Zhang et al 2006;Ribet et al 2008). Each of these genes either uses an LTR as a promoter or contains a MERVL element within 5 kb of its transcriptional start site.…”

“…3A-C). Because there are ;500 full-length and nearly 350 protein-coding MERVL elements (Ribet et al 2008), we tested whether activation of these elements was restricted to a small subset or represented a broader population. We found many small nucleotide polymorphisms (SNPs) in the expressed MERVL elements that were increased in Kdm1a mutant cells, indicating that a large number of MERVL elements become activated (Supplemental Fig.…”

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

“…These elements also control gene expression through formation of chimearic transcripts (Fadloun et al, 2013;Peaston et al, 2004;Svoboda et al, 2004;Veselovska et al, 2015). In early embryos, ERVL, ERVK and ERV1 retrotransposons, as well as LINEs, are more highly expressed than ERVL-MaLRs (Fadloun et al, 2013;Ribet et al, 2008).…”

Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes

“…MuERV-L is a recent endogenous retrovirus that no longer retrotransposes although it produces virus-like particles (Bénit et al 1997;Costas 2003;Ribet et al 2008). MuERV-L LTRs are annotated as MT2_Mm LTRs and share sequence similarity with members of the MT2 family (MT2A-C) and MaLR LTRs, suggesting a common ancestry (McCarthy and McDonald 2004;Hubley et al 2016).…”