The growth and differentiation of the conceptus (embryo/fetus and associated extraembryonic placental membranes) is required in mammals for successful pregnancy. The placenta is essential for transfer of nutrients and gases to the embryo/fetus from the mother. Our long-term goal is to understand the cellular and molecular mechanisms of conceptus development and placental morphogenesis in order to provide fundamental knowledge that will be used to develop rational therapies for the prevention and clinical treatment of pregnancy loss and diseases involving placental dysgenesis, dysplasia, and dysfunction. This research proposal specifically focuses on the biological roles of endogenous retroviruses (ERVs) in conceptus development and placental morphogenesis. ERVs account for about 8% of the genome of every animal species. A number of ERVs are expressed in the human placenta and are associated with placental differentiation and pregnancy diseases such as preeclampsia. However, studies to determine the role(s) of ERVs in humans are not feasible for obvious ethical reasons. In this research project, experiments are designed to determine the biological role(s) of endogenous betaretoviruses during the peri-implantation period of conceptus development and placental morphogenesis in sheep. Sheep harbor endogenous betaretroviruses (termed endogenous Jaagsiekte Sheep Retroviruses or enJSRVs) that are specifically and highly expressed in the uterine endometrial epithelia and placenta. Hyaluronidase 2 (HYAL2), a cellular receptor for JSRV and enJSRV Env, is expressed only by the trophoblast giant binucleate cells and multinucleated syncytia of the placenta. Inhibition of enJSRVs Env expression in the sheep conceptus in vivo retards trophoblast growth, inhibits trophoblast giant binucleate cell differentiation, and compromises early pregnancy. The central hypothesis is that enJSRVs Env and HYAL2 regulate mononuclear trophoblast cell proliferation, differentiation of binucleate cells, and formation of multinucleated syncytia. The experiments utilize novel ideas and research approaches to determine the biological role of enJSRVs and the Hyal2 cellular receptor in trophoblast growth and differentiation. Successful completion of the experiments is expected to elucidate regulatory mechanisms controlling fundamental processes essential for the establishment and maintenance of pregnancy that are regulated by endogenous retroviruses.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Yoshinaga, Koji
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Project End
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Fiscal Year
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Texas A&M University
Veterinary Sciences
Schools of Earth Sciences/Natur
College Station
United States
Zip Code
Armezzani, Alessia; Varela, Mariana; Spencer, Thomas E et al. (2014) ""Ménage à Trois"": the evolutionary interplay between JSRV, enJSRVs and domestic sheep. Viruses 6:4926-45
Spencer, Thomas E; Palmarini, Massimo (2012) Endogenous retroviruses of sheep: a model system for understanding physiological adaptation to an evolving ruminant genome. J Reprod Dev 58:33-7
Spencer, Thomas E; Palmarini, Massimo (2012) Application of next generation sequencing in mammalian embryogenomics: lessons learned from endogenous betaretroviruses of sheep. Anim Reprod Sci 134:95-103
Armezzani, Alessia; Arnaud, Frédérick; Caporale, Marco et al. (2011) The signal peptide of a recently integrated endogenous sheep betaretrovirus envelope plays a major role in eluding gag-mediated late restriction. J Virol 85:7118-28
Black, Sarah G; Arnaud, Fredrick; Palmarini, Massimo et al. (2010) Endogenous retroviruses in trophoblast differentiation and placental development. Am J Reprod Immunol 64:255-64
Spencer, T E; Black, S G; Arnaud, F et al. (2010) Endogenous retroviruses of sheep: a model system for understanding physiological adaptation to an evolving ruminant genome. Soc Reprod Fertil Suppl 67:95-104
Black, Sarah G; Arnaud, Frederick; Burghardt, Robert C et al. (2010) Viral particles of endogenous betaretroviruses are released in the sheep uterus and infect the conceptus trophectoderm in a transspecies embryo transfer model. J Virol 84:9078-85
Arnaud, Frederick; Black, Sarah G; Murphy, Lita et al. (2010) Interplay between ovine bone marrow stromal cell antigen 2/tetherin and endogenous retroviruses. J Virol 84:4415-25
Varela, Mariana; Spencer, Thomas E; Palmarini, Massimo et al. (2009) Friendly viruses: the special relationship between endogenous retroviruses and their host. Ann N Y Acad Sci 1178:157-72
Chessa, Bernardo; Pereira, Filipe; Arnaud, Frederick et al. (2009) Revealing the history of sheep domestication using retrovirus integrations. Science 324:532-6

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