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Knockout Uterus Demonstrate That Implantation but Not Decidualization-Associated Signaling Is Estrogen Dependent
a Laboratory of Reproductive and Developmental Toxicology, NIEHS, NIH, Research Triangle Park, North Carolina 27709
Ovarian hormonal signaling is essential for proper functioning of the uterus in the establishment of pregnancy. Previous studies have demonstrated that decidualization, a stromal transformation that occurs in response to embryo implantation, can be elicited in the uterus of estrogen receptor 
knockout (ERKO) mice in the absence of the estrogen dependence normally seen in wild-type (WT) mice for this response. While the ERKO stromal compartment demonstrated the necessary decidual response, embryo implantation is a process initiated in the epithelial layer, a uterine component that lacks estrogen responsiveness in the ERKO. To determine if the ERKO uterus would be competent for implantation, donor embryos were transferred into the uterine lumen of WT and ERKO females that had been ovariectomized and treated with exogenous estradiol and progesterone to mimic early pregnancy. No implantation occurred in the ERKO, while implantation sites containing live embryos were seen in similarly treated WT uteri, indicating that functional estrogen receptor (ER) is required for implantation. Previous observations of estrogen-independent decidualization in the ERKO prompted investigation of the mechanism leading to estrogen independence of this process. The disruption of progesterone receptor (PR), Hoxa10, Cox2, or LIF in transgenic mice results in the loss of decidualization response. Therefore, the expression of these genes was studied in WT and ERKO uteri by comparing expression following vehicle, progesterone alone (P), or estradiol priming followed by progesterone with nidatory estradiol (E+Pe) and by comparing expression following the above hormonal manipulations in addition to luminal infusion of oil used previously as decidualization-initiating stimulus. The whole-uterus level of PR and Hoxa10 mRNAs did not vary; however, the PR protein was induced in the stroma 24 h after oil infusion. Interestingly, in the WT, this induction was most apparent in samples receiving E+Pe, while in the ERKO samples, the induction occurred independent of any hormone priming. Cox2 protein and mRNA increased in both WT and ERKO samples 2 h after oil infusion in all three of the treatment groups. In the WT samples, Cox2 levels remained elevated 24 h after oil infusion only in the E+Pe treatment group; however, the elevated Cox2 was seen in samples taken 24 h after oil infusion in all three ERKO treatment groups. The ERKO uterine tissue appeared to sustain more extensive damage when examined 24 h after oil infusion. Severe trauma, such as crushing of the uterine tissue, has previously been shown to remove the requirement for nidatory estradiol for deciduomas to develop, indicating that the greater susceptibility of ERKO uterine tissue to damage from intraluminal oil infusion is contributing to decidualization in the absence of ER. Leukemia inhibitory factor (LIF) mRNA was also induced following estradiol treatment in the WT, but also following oil infusion in WT samples that were not treated with estradiol. In contrast, estradiol does not induce LIF mRNA in the ERKO, but oil infusion leads to a robust increase in LIF in all ERKO sample groups. LIF binds and activates its membrane receptor, which initiates responses including the phosphorylation and nuclear translocation of Stat3 transcription factor. Thus, Stat3 phosphorylation was studied in WT and ERKO samples and found to be induced following oil infusion in all samples. Together, these and previous observations illustrate that estrogen is essential for epithelial proliferation and embryo implantation and that estrogen is dispensable for stromal decidualization in the ERKO, as the essential genes and signals required for the response are still induced.
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