The role of ovine betaretroviruses in uteroplacental function

Endogenous retroviruses (ERVs) account for a substantial portion of the genetic pool of every animal species (e.g. ~ 8% of the human genome). Despite their overwhelming abundance in nature, many questions on the basic biology of ERVs are unanswered. Sheep harbor approximately 20 copies of endogenous betaretroviruses (enJSRVs), which are related to an exogenous oncogenic virus, Jaagsiekte sheep retrovirus (JSRV). Therefore, they are an attractive model for investigation of the potential beneficial roles of ERVs in reproductive biology. Studies were conducted to determine: 1) expression of enJSRVs envelope (env) and HYAL2 mRNAs in the ovine uterus and conceptus (embryo/fetus and extraembryonic membranes) throughout gestation; 2) regulation of enJSRVs expression by progesterone; and 3) the role of enJSRVs in regulating peri-implantation placental growth and differentiation. Study One determined the localization of enJSRVs env and HYAL2 mRNAs throughout gestation. Results demonstrate that alterations in expression of enJSRVs and HYAL2 in the sheep uterus and placenta suggest the probability of a variety of physiological roles in implantation and placentation. Partial sequencing of the transcriptionally active enJSRVs from ovine uteroplacental tissues revealed expression of multiple enJSRV loci. Study Two assessed the influence of progesterone, interferon tau, and pregnancy stage on enJSRVs expression, as an effort to understand factors that may regulate enJSRVs. Results of this study support the hypothesis that expression of enJSRVs is modulated by progesterone, but not IFNτ in vivo. Study Three provides for enJSRVs regulating trophectoderm growth and differentiation in the peri-implantation conceptus. Blocking conceptus enJSRVs Env expression compromised pregnancy by retarding trophoblast outgrowth and differentiation. Inhibition of enJSRVs Env in vitro also reduced proliferation of mononuclear trophectoderm cells. Consequently, these results demonstrate that enJSRVs Env regulates trophectoderm growth and differentiation in the ovine conceptus, strongly supporting the biological significance of ERVs in placental evolution and animal reproduction Collectively, these studies illustrate that enJSRVs play an integral role in success of pregnancy. While the definitive roles of the enJSRVs have not yet been elucidated, it is evident that enJSRVs are an important component of the ovine genome and that they influence recognition and maintenance of pregnancy and placental formation