scholarly journals Overlapping and Distinct Expression of Progesterone Receptors A and B in Mouse Uterus and Mammary Gland during the Estrous Cycle

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5503-5512 ◽  
Author(s):  
Patricia A. Mote ◽  
Rebecca L. Arnett-Mansfield ◽  
Natalie Gava ◽  
Anna deFazio ◽  
Biserka Mulac-Jericevic ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Estrous Cycle ◽  
Adult Mouse ◽  
Progesterone Receptors ◽  
Receptor Expression ◽  
Luminal Epithelium ◽  
Mouse Uterus ◽  
Hormone Exposure ◽  
Luminal Cells ◽  
The Individual

In rodents, progesterone receptors (PRs) A and B have different and often nonoverlapping roles, and this study asked whether different activities of the PR proteins in mouse are related to differences in their expression in reproductive tissues. The individual expression of PRA and PRB was determined immunohistochemically in mammary gland and uterus during the estrous cycle or in response to endocrine manipulation. In the mammary gland, PRA and PRB were colocated in PR+ epithelial cells, with little change during the estrous cycle. In the uterus, PRA was not detected in luminal epithelium at any stage of the cycle, and PR+ luminal cells expressed only PRB. In the stroma and myometrium, PRA and PRB levels fluctuated with cyclical systemic hormone exposure. Observation of functional end points suggested that augmented stromal and/or myometrial PRA in proestrus inhibited estrogen receptor expression and epithelial proliferation. Colocation of PRA and PRB was hormonally regulated, and ovariectomy did not reproduce the expression of PRA and PRB in the uterus during the estrous cycle. Whereas PRB was the only PR in the luminal epithelium in cycling mice, ovariectomy restored PRA expression, resulting in PRA-PRB colocation. In stroma and myometrium, PRA and PRB colocated in PR+ cells, but ovariectomy reduced PRA levels more than PRB, resulting in PRB-only-expressing cells. This study has shown that nonoverlapping PRA and PRB expression in the uterus, in particular the lack of PRA, and expression of PRB only in the luminal epithelium throughout the estrous cycle, is likely to contribute to the distinct roles of PRA and PRB in the adult mouse.

scholarly journals Estrogen-triggered delays in mammary gland gene expression during the estrous cycle: evidence for a novel timing system

2006 ◽  
Vol 190 (2) ◽  
pp. 225-239 ◽  
Author(s):  
Gary B Silberstein ◽  
Katharine Van Horn ◽  
Eva Hrabeta-Robinson ◽  
Jennifer Compton
Keyword(s):  
Transcription Factors ◽  
Mammary Gland ◽  
Estrous Cycle ◽  
Time Course ◽  
Progesterone Receptors ◽  
Turnover Time ◽  
Delay Systems ◽  
Mammary Tissue ◽  
Timing System ◽  
Timing Function

During the estrous cycle and beginning in estrus, the mammary gland undergoes pregnancy-like development that depends on transcriptional regulation by the estrogen and progesterone receptors (ER, PR) and Pax-2 as well as the action of the growth factors Wnt-4 and RANKL. In this report, we first describe the decay and delayed expression of ERα, PR, and Pax-2 proteins as well as depression of Wnt-4 and RANKL mRNA coincident with the strong estrogen surge in proestrus. In time-course studies using ovari-ectomized mice, a single estrogen injection replicated these delays and caused an 18 h delay in Wnt-4 expression. Molecular time-delay systems are at the core of cellular cycles, most notably the circadian clock, and depend on proteasome degradation of transcriptional regulators that exhibit dedicated timing functions. The cytoplasmic dynamics of these regulators govern delay duration through negative transcription/translation feedback loops. A proteasome inhibitor, PS-341, blocked estrogen-stimulated ERα, PR, and Pax-2 decay and proteasome chymotryptic activity, assayed using a fluorogenic substrate, was elevated in proestrus correlating with the depletion of the transcription factors. The 18-h delay in Wnt-4 induction corresponded to the turnover time of Pax-2 protein in the cytoplasm and was eliminated in Pax-2 knockout mammary tissue, demonstrating that Pax-2 has a unique timing function. The patterns of estrogen-triggered ERα, PR, and Pax-2 turnover were consistent with a negative transcriptional feedback. Retarding the expression of ERα, PR, and Pax-2 may optimize preparations for pregnancy by coordinating expression of critical receptors and transcription factors with rising estrogen and progesterone levels in estrus. The estrogen surge in proestrus has no defined mammotropic function. This study provides the first evidence that it is a synchronizing signal triggering proteasome-dependent turnover of mammary gland ERα, PR, and Pax-2. We hypothesize that the delays reflect a previously unrecognized timing system, which is present in all ovarian target tissues.

scholarly journals Reproductive tissue selective actions of progesterone receptors

Reproduction ◽  
2004 ◽  
Vol 128 (2) ◽  
pp. 139-146 ◽  
Author(s):  
Biserka Mulac-Jericevic ◽  
Orla M Conneely
Keyword(s):  
Mammary Gland ◽  
Target Genes ◽  
Progesterone Receptors ◽  
Normal Mammary Gland ◽  
Female Reproduction ◽  
Biological Responses ◽  
Gland Morphogenesis ◽  
The Individual

The steroid hormone, progesterone, plays a central coordinate role in diverse events associated with female reproduction. In humans and other vertebrates, the biological activity of progesterone is mediated by modulation of the transcriptional activity of two progesterone receptors, PR-A and PR-B. These receptors arise from the same gene and exhibit both overlapping and distinct transcriptional activitiesin vitro. To delineate the individual roles of PR-A and PR-Bin vivo, we have generated mouse models in which expression of a single PR isoform has been ablated. Analysis of the reproductive phenotypes of these mice has indicated that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive responses to progesterone. While selective ablation of the PR-A protein (PR-A knockout mice, PRAKO mice) shows normal mammary gland response to progesterone but severe uterine hyperplasia and ovarian abnormalities, ablation of PR-B protein (PRBKO mice) does not affect biological responses of the ovary or uterus to progesterone but results in reduced pregnancy-associated mammary gland morphogenesis. The distinct tissue-specific reproductive responses to progesterone exhibited by these isoforms are due to regulation of distinct subsets of progesterone-dependent target genes by the individual PR isoforms. This review will summarize our current understanding of the selective contribution of PR isoforms to the cellular and molecular actions of progesterone in reproductive tissues.

193 Melatonin implants in spring improve embryo production of aged ewes after superovulation regardless of endometrial progesterone receptor expression

2019 ◽  
Vol 31 (1) ◽  
pp. 221
Author(s):  
J. A. Abecia ◽  
A. Meikle ◽  
M. I. Vázquez ◽  
A. Casao ◽  
F. Forcada ◽  
...  
Keyword(s):  
Embryo Quality ◽  
Progesterone Receptors ◽  
Cell Types ◽  
Staining Intensity ◽  
Receptor Expression ◽  
Ovulation Rate ◽  
Corpora Lutea ◽  
Melatonin Treatment ◽  
Embryo Production ◽  
The Individual

Twenty-three Rasa Aragonesa aged ewes (average age: 10.3±0.3 years) were used to determine the effect of melatonin on ovulatory response, embryo production, and endometrial expression of progesterone receptors (PR) after superovulation. Ewes were treated (M, n=13) or not (control, C, n=10) with melatonin implants in March (Day 0, Northern Hemisphere autumn), and received intravaginal progestogen sponges for 14 days on Day 77. Superovulatory treatments consisted of 8 doses in decreasing concentrations (2 mL×2 and 1 mL×6) of 176 NIH-FSH-S1 units of NIADDK-oFSH-17 (Ovagen, ICPbio Reproduction, Auckland, New Zealand) administered twice daily starting 72h before sponge removal. Seven days after oestrus, embryos were recovered by laparotomy, ewes were killed, and uterine horns were processed to study PR expression by immunohistochemistry. The amount of PR was estimated subjectively by 2 independent observers in 5 endometrial compartments: luminal epithelium (LE), superficial (sGE) and deep (dGE) glandular epithelia, and superficial (sS) and deep (dS) stroma. The extent of staining was expressed on a scale from 0 to 100. Data were analysed with a 2×2 factorial ANOVA. Melatonin implants improved fertilization (92v. 57%, for M and C groups, respectively; P<0.01), blastocyst (47v. 9%; P<0.01), viability (88v. 31%; P<0.0001), and freezability (69v. 21%; P<0.001) rates. Specifically, melatonin induced a significant reduction of the number of non-viable (degenerate and retarded) embryos (0.3v. 1.5; P<0.05) and increased blastocysts (2.8v. 0.8; P<0.05) per ewe. Melatonin treatment decreased PR staining intensity (47v. 55%; P<0.05), but this effect was not observed when the individual cell types were compared (Table 1). Because the number of corpora lutea (CL) was responsible for different PR expression in both groups (P<0.0001), animals were divided into 2 ovulation rate categories: <10 CL and ≥10 CL, with lesser PR expression in the ≥10 CL group (P<0.0001); this lower PR immunostaining in ≥10 CL is consistent with progesterone down-regulation of its own receptor. An interaction among number of CL and treatment was found for embryo quality (P<0.05); thus, the positive effect of melatonin on this parameter was particularly effective in the low-ovulation-rate group. These results demonstrate that melatonin treatment in the autumn improves embryo quality in aged ewes, and that this effect is not explained by a differential endometrial sensitivity to progesterone. Table 1.Embryo production (mean±s.e.m.) in melatonin-treated (M) and control (C) ewes after superovulation in autumn, and staining intensity of progesterone receptors in the endometrium (CL=corpora lutea)

scholarly journals Secreted phosphoprotein 1 (osteopontin) is expressed by stromal macrophages in cyclic and pregnant endometrium of mice, but is induced by estrogen in luminal epithelium during conceptus attachment for implantation

Reproduction ◽  
2006 ◽  
Vol 132 (6) ◽  
pp. 919-929 ◽  
Author(s):  
Frankie J White ◽  
Robert C Burghardt ◽  
Jianbo Hu ◽  
Margaret M Joyce ◽  
Thomas E Spencer ◽  
...  
Keyword(s):  
Estrous Cycle ◽  
Immune Cells ◽  
Luminal Epithelium ◽  
Apical Surface ◽  
Wild Type ◽  
Mouse Uterus ◽  
Ovariectomized Mice ◽  
Vaginal Plug ◽  
Secreted Phosphoprotein 1

Secreted phosphoprotein 1 (SPP1, osteopontin) is the most highly upregulated extracellular matrix/adhesion molecule/cytokine in the receptive phase human uterus, and Spp1 null mice manifest decreased pregnancy rates during mid-gestation as compared with wild-type counterparts. We hypothesize that Spp1 is required for proliferation, migration, survival, adhesion, and remodeling of cells at the conceptus–maternal interface. Our objective was to define the temporal/spatial distribution and steroid regulation of Spp1 in mouse uterus during estrous cycle and early gestation.In situhybridization localizedSpp1to luminal epithelium (LE) and immune cells. LE expression was prominent at proestrus, decreased by estrus, and was nearly undetectable at diestrus. During pregnancy,Spp1mRNA was not detected in LE until day 4.5 (day 1 = vaginal plug).Spp1-expressing immune cells were scattered within the endometrial stroma throughout the estrous cycle and early pregnancy. Immunoreactive Spp1 was prominent at the apical LE surface by day 4.5 of pregnancy and Spp1 protein was also co-localized with subsets of CD45-positive (leukocytes) and F4/80-positive (macrophages) cells. In ovariectomized mice, estrogen, but not progesterone, inducedSpp1mRNA, whereas estrogen plus progesterone did not induceSpp1in LE. These results establish that estrogen regulates Spp1 in mouse LE and are the first to identify macrophages that produce Spp1 within the peri-implantation endometrium of any species. We suggest that Spp1 at the apical surface of LE provides a mechanism to bridge conceptus to LE during implantation, and that Spp1-positive macrophages within the stroma may be involved in uterine remodeling for conceptus invasion.

scholarly journals Forkhead box a2 (FOXA2) is essential for uterine function and fertility

2017 ◽  
Vol 114 (6) ◽  
pp. E1018-E1026 ◽  
Author(s):  
Andrew M. Kelleher ◽  
Wang Peng ◽  
James K. Pru ◽  
Cindy A. Pru ◽  
Francesco J. DeMayo ◽  
...  
Keyword(s):  
Stromal Cell ◽  
Adult Mouse ◽  
Embryo Implantation ◽  
Critical Event ◽  
Mouse Uterus ◽  
Forkhead Box ◽  
Uterine Gland ◽  
Blastocyst Implantation ◽  
Uterine Function ◽  
Uterine Glands

Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.

scholarly journals Diet and expression of estrogen alpha and progesterone receptors in the normal mammary gland

2008 ◽  
Vol 20 (5) ◽  
pp. 601-607
Author(s):  
Pagona Lagiou ◽  
Evangelia Samoli ◽  
Areti Lagiou ◽  
Christina Georgila ◽  
Pantelina Zourna ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Progesterone Receptors ◽  
Normal Mammary Gland

scholarly journals Methamphetamine Administration Increases Proceptive Behavior by Activating Src Kinase and Upregulating Progesterone Receptor in the Medial Amygdala

2018 ◽  
Author(s):  
Katrina M Williams ◽  
Sarah A Rudzinskas ◽  
Jessica A Mong
Keyword(s):  
Progesterone Receptor ◽  
Phosphorylation Site ◽  
Progesterone Receptors ◽  
Receptor Expression ◽  
Medial Amygdala ◽  
Specific Manner ◽  
Receptor Action ◽  
Necessary And Sufficient ◽  
Motivated Behaviors

Methamphetamine, a psychostimulant drug of abuse, increases sexual motivation both in humans and in rodent models. The activation of dopamine type-1 receptors (D1Rs) within the medial amygdala, in the presence of ovarian hormones (EB+P), are both necessary and sufficient for increases in proceptive, or sexually motivated, behaviors. Here, we demonstrate that methamphetamine increases progesterone receptor expression in the medial amygdala independently of D1R activation, and that lentiviral overexpression of the progesterone receptor was able to recapitulate the methamphetamine-induced enhancement of proceptive behaviors. Furthermore, we found that within the medial amygdala, these progesterone receptors show an increase in phosphorylation of serine 294 of the progesterone receptor in a region-specific manner. The involvement of this phosphorylation site suggests a role for cytosolic kinases, which may be responsible for enhanced progesterone receptor action. The phosphorylation of serine 294 is blocked by D1R antagonists, and by inhibiting cSrc and ERK1/2, downstream of D1R signaling, we identified that Src and ERK1/2 are required for enhanced proceptive behavior. Taken together, we propose that within the medial amygdala, methamphetamine enhances progesterone receptors sensitivity to its cognate ligand via interaction with cSrc kinase and ERK1/2, as well as an increase total progesterone receptors, thus leading to enhanced proceptive behaviors in the rat.

HYPERTROPHY AND HYPERPLASIA IN THE MOUSE UTERUS AFTER OESTROGEN TREATMENT: AN AUTORADIOGRAPHIC STUDY

1973 ◽  
Vol 56 (1) ◽  
pp. 133-NP ◽  
Author(s):  
L. MARTIN ◽  
C. A. FINN ◽  
GAIL TRINDER
Keyword(s):  
Cell Death ◽  
Dna Synthesis ◽  
Proliferative Response ◽  
Autoradiographic Study ◽  
Luminal Epithelium ◽  
Uterine Tissue ◽  
Mouse Uterus ◽  
Oestrogen Treatment ◽  
Ovariectomized Mice

SUMMARY The uteri of untreated ovariectomized mice consisted almost entirely of myometrium and connective tissue stroma. After oestrogenic stimulation these tissues underwent marked hypertrophy, but showed little proliferation. The luminal epithelium underwent marked hyperplasia, with most cells dividing twice to quadruple cell numbers by 35–40 h, when they made up 10–12% of the uterine tissue volume and 20% of the total uterine cell population. The proliferative response was rapid, highly synchronized and short-lived. The number of cells incorporating [3H]thymidine first increased 8·5 h after oestradiol-17β and by 13–16 h 60–70% were engaged in DNA synthesis. Up to 21 h cell-death was minimal. From 21 h onwards the proliferation rate declined and the rate of cell death increased. A second injection of oestrogen prevented the rise in death rate and produced a second smaller burst of DNA synthesis. Cells in DNA synthesis or mitosis were insensitive to oestrogen. A smaller proliferative response occurred in the glands: only 25% of cells entered DNA synthesis after the first injection of oestradiol and none after the second. Gland cells appeared to die in situ and there was no evidence that they migrated into the luminal epithelium.

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