Figure 2

Schematic illustrating the current working hypothesis on the hormonal servomechanism regulating uterine gland morphogenesis and function in the ovine endometrium during pregnancy. Interferon tau (IFNτ) is produced by the conceptus between Days 11 and 21–25 of pregnancy with maximal production on Days 15–16. High levels of endogenous Jaagsiekte sheep retroviruses (enJSRVs) are expressed in the PR-positive endometrial LE and GE in response to increasing progesterone to stimulate trophoblast proliferation and production of IFNτ. Continuous exposure of the endometrium to progesterone for 8 to 10 days negatively autoregulates PR expression, so that LE and GE are PR-negative by Days 11 and 13, respectively. IFNτ activates the JAK-STAT pathway in the endometrial glands which stimulates formation of STAT1 homodimers (or GAF) as well as the transcription factor IFN stimulated gene factor 3 (ISGF3; heterotrimer of STAT1, STAT2 and IRF-9). STAT1 homodimers or GAF transactivate a GAS element in the IRF-1 gene. IRF-1 then binds to IRF-Es and transactivates the UTMP promoter. ISGF3 transactivates ISREs present in the 2',5' oligoadenylate synthetase (OAS) gene. The 40/46-kDa form of OAS interacts with the intracellular domain of the prolactin receptor (PRLR), which mediates the actions of ovine PL. Specifically, OAS prevents PRLR signaling to STAT1 and promotes signaling through STAT5. Ovine PL is produced by the conceptus beginning on Days 16–17 of pregnancy, which is concomitant with the formation of binucleate cells in the trophectoderm. The actions of PL are mediated by PRLR homodimers or perhaps heterodimers of PRLR and growth hormone receptor (GHR) that stimulate formation of STAT5 homodimers. STAT5 dimers bind and transactivate the GAS element in the UTMP promoter. The induction of UTMP gene expression in the GE by IFNτ-stimulated IRF-1 is maintained by the actions of PL through STAT5.