Rapid expression of RASD1 is regulated by estrogen receptor-dependent intracellular signaling pathway in the mouse uterus (original) (raw)
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Biology of Reproduction, 2002
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.
PloS one, 2016
Embryo implantation is an essential step for the establishment of pregnancy and dynamically regulated by estrogen and progesterone. NDRG4 (N-myc down-regulated gene 4) is a tumor suppressor that participates in cell survival, tumor invasion and angiogenesis. The objective of this study was to preliminarily explore the role of NDRG4 in embryo implantation. By immunohistochemistry (IHC) and quantitive RT-PCR (qRT-PCR), we found that uterine expression of NDRG4 was increased along with puberal development, and its expression in adult females reached the peak at the estrus stage during the estrus cycle. Furthermore, uterine NDRG4 expression was significantly induced by the treatment of estradiol (E2) both in pre-puberty females and ovariectomized adult females. Uterine expression pattern of NDRG4 during the peri-implantation period in mice was determined by IHC, qRT-PCR and Western blot. It was observed that NDRG4 expression was up-regulated during the implantation process, and its expr...
Biology of reproduction, 2015
Progesterone (P4) and the synthetic glucocorticoid dexamethasone (Dex) inhibit luminal epithelial (LE) proliferation in neonatal mouse uteri. This study determined the roles of progesterone receptor and estrogen receptor 1 (PR and ESR1, respectively) in P4- and Dex-induced inhibition of LE proliferation using PR knockout (PRKO) and Esr1 knockout (Esr1KO) mice. Wild-type (WT), heterozygous and homozygous PRKO female pups were injected with vehicle, P4 (40 μg/g BW) or Dex (4 or 40 μg/g BW) on Postnatal Day 5, then 24 h later immunostained for markers of cell proliferation. In WT and heterozygous mice, P4 sharply reduced LE proliferation, and Dex produced dose-responsive decreases equaling those of P4 at the higher dose. Critically, although both doses of Dex similarly decreased proliferation compared to vehicle-treated PRKOs, treatment of PRKO pups with the high Dex dose (40 μg/g) did not inhibit LE as much as this Dex dose or P4 in WT mice. Stromal proliferation was stimulated by P4 ...
Proceedings of the National Academy of Sciences, 1999
Estrogen is known to increase progesterone receptor (PR) levels in the wild-type mouse uterus, and this estrogen induction was thought to be important for progesterone action through the PR. The estrogen receptor ␣ knockout (ERKO) mouse uterus was observed to express PR mRNA that cannot be induced by estrogen. Progesterone action was characterized to determine whether it was diminished in ERKO mice. The PR protein is present in the ERKO uterus at 60% of the level measured in a wild-type uterus. The PR-A and PR-B isoforms are both detected on Western blot, and the ratio of isoforms is the same in both genotypes. Although the level of PR is reduced in the ERKO uterus, the receptor level is sufficient to induce genomic responses, since both calcitonin and amphiregulin mRNAs were increased after progesterone treatment. Finally, the ERKO uterus can be induced to undergo a progesterone-dependent decidual response. Surprisingly, the decidual response is estrogen independent in the ERKO, although it remains estrogen dependent in a wild type. These results indicate that estrogen receptor ␣ modulation of PR levels is not necessary for expression of the PR or genomic and physiologic responses to progesterone in the ERKO uterus.
Steroids, 2009
Endometriosis, defined as the presence of endometrial glands and stroma at extra-uterine sites, is a gynecological condition that affects women of reproductive age. Consistent with its uterine origins, endometriotic lesions and resulting symptoms are hormonally responsive. To investigate Progesterone Receptor (PR)-based therapies, we measured physiological endpoints and gene expression in rat models of uterine cell estrogenic activity. Estrogen-induced ELT-3 rat leiomyoma cell proliferation was significantly inhibited by progesterone (P4), while the antiprogestin RU486 or the Selective PR Modulator (SPRM) asoprisnil, did not block proliferation. Stromal cell-derived factor-1 (SDF-1/Cxcl12) gene expression was induced by estrogen, and was repressed by the Selective Estrogen Receptor Modulators (SERMs), the antiestrogen ICI 182,780, and P4, but not by RU486 or the ER-selective ligand ERB-041. In ELT-3 cells, asoprisnil demonstrated partial PR agonism on SDF-1 gene repression. Magnetic Resonance Imaging was used to monitor development of ectopic cysts in a rat surgical model of endometriosis. SERMs and P4 significantly decreased cyst volumes comparably by ∼60%. However, ERB-041 and asoprisnil had no effect on cyst volume, and RU486 increased cyst volume by 20%. SDF-1 expression was modestly, but significantly, increased in the cyst compared to eutopic uterus, and P4 and raloxifene could repress the expression. We showed that SDF-1 was similarly regulated in human cells. These data suggest that transcriptional regulation of SDF-1 is a surrogate marker of estrogenic activities via ER␣ in rat uterine cells, and that SDF-1 repression by PR agonists can predict the ability to oppose the actions of estrogen in vivo.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2003
Estrogens and glucocorticoids have opposing effects on the female reproductive tract, but the molecular basis for this antagonism is poorly understood. We therefore examined the biological and transcriptional programs induced by estrogens and glucocorticoids in the uterus of immature female rats. Estradiol 17beta (E2) rapidly induced morphological changes reminiscent of an acute inflammatory response, including infiltration of eosinophils, edema in the stroma and myometrium, and a decrease in the height of luminal epithelial cells, whereas dexamethasone (Dex) only altered stromal cell morphology. When coadministered with E2, Dex completely blocked the proinflammatory effects of E2. Surprisingly, examination of E2 and Dex effects on gene expression using cDNA microarrays and real-time PCR revealed that these hormones had similar effects on the expression of many genes and that very few genes displayed antagonistic regulation. Together, these results indicate strong discord between th...
Cell-type specific analysis of physiological action of estrogen in mouse oviducts
2020
One of the endogenous estrogens, 17β-estradiol (E2) is a female steroid hormone secreted from the ovary. It is well established that E2causes biochemical and histological changes in the uterus. The oviduct response to E2is virtually unknown in anin vivoenvironment. In this study, we assessed the effect of E2on each oviductal cell type, using an ovariectomized-hormone-replacement mouse model, single cell RNA-sequencing (scRNA-seq),in situhybridization, and cell-type-specific deletion in mice. We found that each cell type in the oviduct responded to E2distinctively, especially ciliated and secretory epithelial cells. The treatment of exogenous E2did not drastically alter the transcriptomic profile from that of endogenous E2produced during estrus. Moreover, we have identified and validated genes of interest in our datasets that may be used as cell- and region-specific markers in the oviduct. Insulin-like growth factor 1 (Igf1) was characterized as an E2-target gene in the mouse oviduct...
Changes in Mouse Uterine Transcriptome in Estrus and Proestrus1
Biology of Reproduction, 2013
Changes in the CD-1 mouse uterine transcriptome during proestrus and estrus were investigated to help elucidate mechanisms of uterine tissue remodeling during the estrus cycle and their regulation by estrogen and progesterone in preparation of the uterus for pregnancy. Mice were staged beginning at 6 weeks of age, and uterine horns were harvested after monitoring two estrus cycles. Microarray analysis of whole uterine horn RNA identified 2428 genes differentially expressed in estrus compared to proestrus, indicating there is extensive remodeling of mouse uterus during the estrus cycle, affecting ;10% of all protein-encoding genes. Many (;50%) of these genes showed the same differential expression in independent analyses of isolated uterine lumenal epithelial cells. Changes in gene expression associated with structural alterations of the uterus included remodeling of the extracellular matrix, changes in cell keratins and adhesion molecules, activation of mitosis and changes in major histocompatibility complex class II (MHCII) presentation, complement and coagulation cascades, and cytochrome P450 expression. Signaling pathways regulated during the estrus cycle, involving ligand-gated channels, Wnt and hedgehog signaling, and transcription factors with poorly understood roles in reproductive tissues, included several genes and gene networks that have been implicated in pathological states. Many of the molecular pathways and biological functions represented by the genes differentially expressed from proestrus to estrus are also altered during the human menstrual cycle, although not necessarily at the corresponding phases of the cycle. These findings establish a baseline for further studies in the mouse model to dissect mechanisms involved in uterine tissue response to endocrine disruptors and the development of reproductive tract diseases.