Endogenous Retroviruses in Trophoblast Differentiation and Placental Development

Abstract

Endogenous retroviruses (ERVs) are present in the genome of all vertebrates and originated from infections of the germline of the host by exogenous retroviruses. ERVs have coevolved with their hosts for millions of years and are recognized to contribute to genome plasticity, protect the host against infection of related pathogenic and exogenous retroviruses, and play a vital role in development of the placenta. Consequently, some ERVs have been positively selected and maintained in the host genome throughout evolution. This review will focus on the critical role of ERVs in development of the mammalian placenta and specifically highlight the biological role of sheep JSRV-related endogenous betaretroviruses in conceptus (embryo and associated extraembryonic membranes) development.

Human endogenous retrovirus K (HERV-K) is expressed in villous and extravillous cytotrophoblast cells of the human placenta

“…Knockout mice for the murine syncytin-A died in utero, indicating that this gene is essential for mouse embryonic development . Endogenous retroviral env genes were also "enslaved" for placental functions in sheep (Black et al, 2010) and rabbits (Heidmann et al, 2009). In the sheep, the envelope gene of endogenous retroviruses related to the Jaagsiekte sheep retrovirus was shown to be involved in placenta evolution and inhibition of their expression by RNA interference compromised conceptus elongation.…”

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).…”

Mechanism of Congenital Chagas Disease: Effective Infection Depends on the Interplay Between Trypanosoma cruzi and the Different Tissue Compartments in the Chorionic Villi of the Human Placenta

“…Mtd-L expression in proliferating cells co-localized with cyclin E1, a G 1 /S phase cell cycle regulator (Ray et al, 2010). b. Caspase 8 is activated in highly differentiated CT just prior to fusion and escorts the fusing cell content including the nucleus into the ST; interestingly, it has not been found in proliferating CT cells (Black et al, 2010;Huppertz and Gauster, 2010;Huppertz and Borges, 2008). c. Activation of caspase-8 induces phosphatidylserine "flip", which is a key signal for syncytial fusion (Huppertz and Gauster, 2010;Huppertz and Gauster, 2011) and for cell death by apoptosis (Savill, 1998).…”

“…Some of these factors, considered as trophoblast "differentiation markers" or "fusion markers", are the following: a. Syncytin family proteins: Syncytins are fusogenic proteins encoded by envelope genes (env genes) of the human endogenous retrovirus (HERV)-W (Syncytin-1), (HERV)-FRD (Syncytin-2), and (HERV)-P(b) (Syncytin-3;) (Ruebner et al, 2010). HERVs contribute to genome plasticity, protect the host against infection with related pathogenic and exogenous retroviruses, and play a vital role in the development of the placenta (Black et al, 2010). Knock down of syncytin-1 inhibited syncytialization of primary trophoblasts (Gauster et al, 2009).…”