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Department of Physiology and Biophysics,3 University of Arkansas for Medical Sciences
Arkansas Children's Nutrition Center,4 Little Rock, Arkansas 72202
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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female reproductive tract, implantation, progesterone, steroid hormone receptors, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Gene ablation in the mouse has revealed the importance of specific genes during the period surrounding implantation [14–17]. Of these, perhaps the most important is that encoding PGR since mice null for Pgr are totally infertile [18]. Interestingly, while ablation of the gene for PGR-A, the shorter (94 kDa) of the two PGR isoforms [19, 20], resulted in severe uterine hyperplasia and ovarian abnormalities, leading to infertility [21], ablation of the gene encoding PGR-B (114 kDa) did not result in an obvious uterine phenotype but rather in pregnancy-associated mammary gland abnormalities [22]; these suggest an obligatory role for PGR-A in reproduction. Nevertheless, distinct subsets of P-target genes for each individual PGR isoform were demonstrated in the uterine endometrium, suggesting a function for both PGR-A and PGR-B in this tissue [21].
Since P has an essential role in establishment and maintenance of pregnancy, factors that affect PGR function and/ or expression markedly alter uterine sensitivity to P and hence pregnancy success. Our laboratory has identified basic transcription element binding protein-1 (BTEB1), a member of the Sp1 family of transcription factors [23], as a novel PGR-interacting protein [24, 25] whose expression in the early pregnancy endometrium was coincident with PGR expression [25, 26]. In subsequent studies, we reported that null mutation of Bteb1 [27] resulted in subfertility in female mice due to multiple effects in the uterus [28]. In particular, we found uterine growth retardation in prepubertal and young adult females, fewer numbers of embryo implantation sites at 6.5 dpc and hence decreased litter size, and partial uterine insensitivity to P-stimulation. These results suggested that BTEB1 may function as a PGR coactivator during peri-implantation, when the P-dominant environment of the uterus necessitates a functional PGR to subserve the timely progression of endometrial cell proliferation and differentiation requisite for endometrial receptivity.
The present study was designed to evaluate the mechanism by which BTEB1, acting in concert with PGR in the endometrial stroma, mediates endometrial receptivity. Toward this end, we examined the consequence of Bteb1 ablation on endometrial cell proliferation and apoptosis as well as on the expression of PGR and ESR1 in ST, the site of predominant BTEB1 expression [28], during peri-implantation. Further, we assessed the sensitivity of the endometrium to E + P, using mice of both Bteb1 genotypes on ovariectomy.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animal protocols were approved by the Institutional Animal Care and Use Committee of the University for Arkansas for Medical Sciences. WT and Bteb1(–/–) mouse lines were propagated and genotyped as previously described [28]. In timed pregnancy studies, WT and Bteb1(–/–) females of comparable ages (6–8 wk) were monitored for stage of the estrous cycle by the appearance of vaginal smears using a Protocol Hema stain kit (Fischer Scientific, Pittsburgh, PA) and were mated at proestrus of the second estrous cycle. The presence of a vaginal plug was considered as 0.5 day postcoitum (dpc). WT and Bteb1(–/–) females were mated with Bteb1(–/–) and WT males, respectively, to generate embryos of the same phenotype (heterozygote); this strategy precluded the possibility that any observed changes in the endometrium of Bteb1(–/–) mice might be due to lack of embryonic BTEB1 expression. For steroid hormone treatment studies, 6- to 8-wk-old adult WT and Bteb1(–/–) females were subjected to bilateral ovariectomy and were then rested for 2 wk before receiving a single subcutaneous injection (0.1 ml) of sesame oil (vehicle) or estradiol-17ß (E; 100 ng/mouse; Sigma Biochemicals, St. Louis, MO) + progesterone (P; 1 mg/mouse; Sigma) in sesame oil. Mice were killed 24 h after injection.
Steroid Hormone Measurements
Serum E and P concentrations for WT and Bteb1(–/–) female mice (n = 5–7 mice per genotype per dpc) were measured using Coat-A-Count Estradiol or Coat-A-Count Progesterone Diagnostic kits following the manufacturer's protocols (Diagnostic Products Corp., Los Angeles, CA) as previously described [28]. All samples were assayed in one run.
Immunocytochemistry and TUNEL Assay
Whole uteri from WT and Bteb1(–/–) females at peri-implantation (dpc = 0.5, 1.5, 2.5, 3.5, 4.5, 5.5; n = 5–6 mice per dpc per genotype) were fixed in 10% neutral-buffered formaldehyde overnight and embedded in paraffin. Procedures for the preparation of tissue sections and staining were previously described [28]. Prior to incubation with primary antibody, sections were treated with 3% hydrogen peroxide to quench endogenous peroxidase activity, microwaved sequentially (105 sec at power 10 and then 10 min at power 1) in Citra Plus (Biogenex, San Ramon, CA) to unmask antigen, and incubated in a blocking solution (VectaStain ABC kits; Vector Laboratories, Burlingame, CA) for 30 min to decrease nonspecific staining. Incubation with rabbit anti-human PGR antibody (1:650 dilution; Dako Corp., Carpinteria, CA) and goat anti-human HOXA10 antibody (1: 1000 dilution; Santa Cruz Biotech, Santa Cruz, CA) were carried out for 1 h and overnight, respectively, at 4°C in a humidity chamber. Incubation with rabbit anti-human ESR1 antibody (1:500 dilution; Santa Cruz) for 1 h at room temperature followed previously described procedures [29], except for the antigen retrieval step and the use of VectaStain kits, as described previously. Following incubation with appropriate anti-goat or anti-rabbit secondary antibodies (Vectastain ABC kits), immunoreactive proteins were detected with the chromagen 3,3'-diaminobenzidine tetrahydrochloride (Dako), and sections were then counterstained with hematoxylin, dehydrated, cleared, and coverslipped for examination under a microscope. A total of 1000 ST, 300 LE, and 200 GE cells, respectively, were counted on average from four randomly selected fields (200x magnification) per slide and two slides for each mouse, with a total of five to six mice per dpc or treatment group used for the analyses.
TUNEL assay to detect apoptotic cells was performed as previously described [30]. The same numbers of ST, GE, and LE cells, as indicated previously, were examined for positive staining per slide and two slides for each mouse, with a total of five to six mice per dpc or treatment group evaluated.
BrdU Labeling
WT and Bteb1(–/–) females at the indicated pregnancy day (0.5–5.5 dpc; n = 5–6 mice per genotype per dpc) or 2 wk after ovariectomy and steroid treatments (n = 5–6 per genotype for sesame oil or E + P) were administered intraperitoneal injections of BrdU reagent (1 ml per 100 g of body weight; Zymed Laboratories, San Francisco, CA) 2 h before sacrifice. Uteri were fixed in 10% neutral-buffered formalin and processed for immunohistochemistry as described previously. BrdU uptake was detected using the BrdU-detection kit following the manufacturer's protocol (Zymed). Immunopositive ST, LE, and GE cells were counted from a total of 1000, 300, and 200 cells, respectively, from four randomly selected fields (200x magnification) per slide and two slides for each mouse, with a total of five to six mice per group used for analyses.
Data Analysis
All data are presented as mean ± SEM. The values were subjected to analysis by Student t-test, one-way ANOVA, or two-way ANOVA, as indicated under each figure legend. Differences between means in one-way and two-way ANOVA were further analyzed by Tukey test. Correlation coefficients were calculated by Spearman rank order correlation. P values < 0.05 were considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Serum levels of E and P in WT mice from 0.5 to 5.5 dpc were in agreement with previously published data for mouse and rat strains [2, 31, 32]. An increase in P levels occurred from 2.5 to 3.5 dpc and then decreased slightly through to 5.5 dpc (Fig. 1A). By contrast, E levels did not significantly change from 0.5 dpc until 4.5 dpc, rising only at 5.5 dpc (Fig. 1C). WT and Bteb1(–/–) females showed comparable serum E (P > 0.5) and P (P > 0.5) levels at each of the time points examined (Fig. 1, B and D).
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Expression of PGR, HOXA10, and ESR1 in Uterine Stroma of WT and Bteb1(–/–) Mice
The expression of PGR (A/B isoforms) and its downstream target HOXA10 were evaluated in uterine ST of pregnant (0.5–5.5 dpc) WT and Bteb1(–/–) mice by immunohistochemistry. In WT mice, the percentage of PGR-expressing ST cells increased temporally from 0.5 dpc to maximal levels at 3.5 dpc, and this level of expression was maintained through 5.5 dpc (Fig. 2, A and B). The percentage of PGR-expressing cells differed between WT and Bteb1(–/–) mice only at 3.5 and 4.5 dpc and was comparable for both genotypes at the other pregnancy days (Fig. 2, A and B). The temporal pattern of HOXA10 immunoreactivity followed that of PGR; the percentage of HOXA10 immunopositive cells increased from 0.5 dpc through 5.5 dpc and was higher in WT than Bteb1(–/–) mice at 3.5 and 4.5 dpc (Fig. 2, C and D).
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The contribution of BTEB1 to ST expression of ESR1 was examined by quantifying the percentage of ESR1-expressing cells in WT and Bteb1(–/–) mice. In contrast to that for PGR, the percentage of ESR1-expressing ST cells was relatively constant throughout early pregnancy (Fig. 3). However, similar to that for PGR, a difference in the percentage of ESR1-expressing ST cells between the two genotypes was observed at 3.5 dpc, although WT exhibited lower numbers of immunopositive cells than Bteb1(–/–) mice (Fig. 3).
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Effect of Bteb1 Null Mutation on Uterine Endometrial Cell Proliferation and Apoptosis
Endometrial cell proliferation in WT and Bteb1(–/–) females from 0.5 to 5.5 dpc was quantified from BrdU-labeled tissue sections by counting the percentage of BrdU-positive cells in LE, GE, and ST. In WT mice, the percentage of BrdU-labeled LE and GE cells was low at 0.5 and 1.5 dpc, increased to maximal levels at 2.5 dpc, dramatically decreased at 3.5 dpc to the levels found for 0.5 dpc, and remained low through 5.5 dpc (Fig. 4). By comparison, BrdU labeling of cells in Bteb1(–/–) mice displayed a different pattern; LE exhibited a delayed peak in cell proliferation that occurred at 3.5 dpc (vs. 2.5 dpc for WT mice), while proliferation in GE was significantly blunted at 2.5 dpc and persisted for 1 day longer (3.5 dpc) than in WT mice. The pattern of ST proliferation also differed between WT and Bteb1(–/–) mice (Fig. 4). While ST cells from WT mouse uteri showed a dramatic increase in percentage of BrdU labeling at 2.5 dpc, which was essentially maintained through 4.5 dpc and then diminished to 0.5 dpc levels by 5.5 dpc, those of Bteb1(–/–) mutants had a delayed increase in BrdU labeling, which peaked at 3.5 dpc.
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Given the effects of Bteb1 ablation on cell proliferation, the apoptotic status of endometrial cells in WT and Bteb1(–/–) mouse uteri was also evaluated (Fig. 5, A and B). For all cell types, the temporal pattern of apoptosis (measured as percentage of TUNEL-positive cells) was comparable between genotypes up to 3.5 dpc, except at 2.5 dpc, when Bteb1(–/–) mutants showed a higher percentage of apoptotic cells relative to WT. After 3.5 dpc, the pattern of apoptosis differed slightly among cell types: GE at 4.5 dpc showed higher apoptosis in WT than in Bteb1(–/–), while ST at 5.5 dpc had higher apoptosis in Bteb1(–/–) than in WT. On the other hand, LE from WT and Bteb1(–/–) mice between 3.5 and 5.5 dpc had undetectable apoptotic cells (Fig. 5A).
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The observed differences in cell proliferation and apoptosis occurring between 2.5 and 3.5 dpc for WT and Bteb1(–/–) mice were temporally correlated with rising serum P levels (which initiates at 2.5 dpc) and with the decrease in percentage of ST PGR-immunopositive cells in Bteb1(–/–) relative to WT mice at 3.5 dpc. To evaluate whether loss of BTEB1 might be linked to alterations in an existent paracrine relationship among these parameters, the correlation between PGR-positive ST cells and proliferation or apoptosis in endometrial LE and GE cells was examined as a function of Bteb1 genotype before (0.5–2.5 dpc) and during and subsequent to (2.5–5.5 dpc) the rise in serum P levels. Between 0.5 and 2.5 dpc, the percentage of PGR-immunopositive ST cells was not correlated with proliferation status in LE (P = 0.442 and 0.304 for WT and Bteb1(–/–), respectively) or GE (P = 0.852 and 0.304 for WT and Bteb1(–/–), respectively) regardless of Bteb1 genotype. By contrast, between 2.5 and 5.5 dpc, there was a strong negative correlation between ST expression of PGR and proliferation of LE (correlation coefficient r = –0.552; P = 0.031) and GE (r = –0.556; P = 0.030), respectively, in WT mice. Interestingly, this correlation was lost with Bteb1 null mutation in LE (r = –0.074; P = 0.783) and in GE (r = –0.360; P = 0.180). A negative correlation between PGR expression in ST and apoptosis in LE was noted in WT and Bteb1(–/–) mice before (WT: r = –0.643; P = 0.022; Bteb1(–/–): r = –0.676; P = 0.010) and after (WT: r = –0.778; P < 0.001; Bteb1(–/–): r = –0.766; P < 0.001) the rise in P levels. The negative correlation in WT mice (r = –0.587; P = 0.042) between PGR expression in ST and GE apoptosis was also observed in Bteb1(–/–) (r = –0.648; P = 0.016) mice at low P but was lost in WT (r = –0.081; P = 0.708) when compared to Bteb1(–/–) (r = –0.638; P = 0.010) mice, under conditions of high P.
Effect of BTEB1 Null Mutation on Endometrial Cell Responsiveness to E and P
Given the altered proliferation in uterine LE, GE, and ST of Bteb1(–/–) relative to WT mice, in the background of comparable serum E and P profiles, we tested whether loss of responsiveness to exogenous E + P may underlie these differences between genotypes. Ovariectomy of WT and Bteb1(–/–) mice resulted in low basal levels of proliferation in all three uterine cell types for both Bteb1 genotypes. After 24 h of exposure to E + P, dramatic increases in BrdU labeling were observed for LE (by 30-fold) and GE (by 6-fold) in WT uteri (Fig. 6, A and B). By comparison, GE cells of Bteb1(–/–) mouse uteri did not show any increase in BrdU labeling, while LE cells displayed an increase that was 50% lower than observed in WT. Stromal cells from OVX WT mouse uteri, although responsive to E + P, had a lower degree of induced proliferation when compared to LE and GE cells, respectively; by comparison, ST cells from corresponding Bteb1(–/–) uteri were unresponsive to this treatment (Fig. 6C).
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Uterine LE and GE cells of OVX WT mice had comparable levels of apoptosis that were significantly diminished with E + P treatments (Fig. 7). Ablation of Bteb1 did not influence their apoptotic responses to E + P. By contrast, uterine ST cells in OVX WT mice displayed higher levels of apoptosis than in those of OVX Bteb1(–/–) mice; E + P treatment reduced the level of apoptosis in WT uteri but had no effect in uteri of Bteb1(–/–) mice.
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To evaluate whether blunted (LE) or loss of (GE, ST) proliferative responses to E + P could be a function of BTEB1-mediated regulation of PGR or ESR1 expression in ST, the percentage of ST cells expressing PGR, HOXA10, and ESR1 was evaluated in control and E + P-treated cells from uteri of WT and Bteb1(–/–) mice. OVX WT and Bteb1(–/–) mice had comparable ST expression of PGR, HOXA10, and ESR1 (Fig. 8). Treatment of WT mice with E + P increased the numbers of ST cells expressing PGR (Fig. 8A), HOXA10 (Fig. 8B), and ESR1 (Fig. 8C). By comparison, in uteri of OVX Bteb1(–/–) mice, the percentage of ST cells expressing HOXA10 and ESR1 was not altered with E + P treatment, while that of PGR-expressing cells in ST was increased, albeit 50% lower than in uteri from OVX, E + P-treated WT mice (Fig. 8).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our hypothesis of the involvement of ST BTEB1, acting in concert with ligand-bound PGR in the control of ST and LE cell proliferation at peri-implantation, is supported by a number of observations from this and previous studies. First, we have shown that BTEB1 expression in early pregnant mouse uteri was predominantly in ST, with undetectable expression in LE [28]. Moreover, ST expression of BTEB1 was found to be dependent on pregnancy day, with 3.5 dpc showing higher level of expression relative to 0.5 dpc, respectively [28], a pattern paralleled by ST PGR (this study). Second, LE proliferation during early pregnancy in the mouse has been reported to be negatively regulated by PGR in the ST [33, 34]. Consistent with this, we found that at 2.5 and 3.5 dpc, when the most dramatic differences in LE proliferation between WT and Bteb1(–/–) were observed, there was no difference in the percent of PR-expressing LE cells in uteri of mice of either Bteb1 genotype (data not shown). Third, we report here that the number of PGR-expressing ST cells is negatively correlated with LE proliferation at or after 2.5 dpc (coincident with the initiation in rising P levels), and this correlation was lost with Bteb1 ablation. Last, we observed that the number of ST cells expressing PGR was greater in both pregnant and OVX, E + P-treated WT mice, relative to Bteb1(–/–) mice, suggesting that establishment and/or maintenance of threshold levels of functional PGR by BTEB1 in ST is important for control of LE proliferation. Interestingly, the control of apoptosis by BTEB1 at peri-implantation appeared to be independent of P-bound PGR and varied with cell type, suggesting that although cell proliferation and cell death may be coordinately regulated by BTEB1 during early pregnancy, distinct mechanisms are involved.
The negative correlation between ST PGR and LE proliferation that was demonstrated in WT but not Bteb1(–/–) mice was observed only at or after the rise in serum P levels. Prior to this time (earlier than 2.5 dpc), this correlation was nonexistent, regardless of BTEB1 genotype. In particular, maximal proliferation of LE cells in WT occurred at 2.5 dpc, when ST PGR and serum P levels are coincidentally low, suggesting that under conditions of low (or no) PGR activation by its ligand P, BTEB1 in ST positively affected LE cell proliferation. Consistent with this, we have shown in an earlier study [35] that stable transfection of BTEB1 expression construct in a human endocarcinoma cell line Hec-1A lacking PGR resulted in increased cell proliferation coincident with up-regulated expression of positively acting growth regulatory genes [35, 36]. Moreover, we also demonstrated that cotransfection of PGR expression constructs in the Hec-1A clonal line expressing high levels of BTEB1 resulted in increased promoter activity of a P-dependent gene, uteroferrin, whose expression is associated with uterine differentiation [24]. Hence, we suggest that BTEB1 plays a dual role in the control of uterine development; under a PGR/P-independent cellular context, BTEB1 mainly exhibits proliferative activity, while under conditions where levels of activated (functional) PGR are high, BTEB1 interacts with the PGR/ P complex to induce cell differentiation. The latter is supported by our present finding that ST expression of the PGR/P-downstream target gene Hoxa10, which encodes a homeodomain transcription factor important for development of endometrial receptivity [14], is altered in Bteb1(–/–) mice only at 3.5 and 4.5 dpc. Thus, the regulation of uterine development at peri-implantation, specifically of the LE, may involve ST-derived factors whose temporal expression is regulated by BTEB1 but to differing extents by PGR/P.
The ability of BTEB1 to affect the proliferation as well as apoptosis of the three major endometrial cell types at peri-implantation and in OVX mice treated with E + P demonstrates that this transcription factor affects endometrial sensitivity to steroid hormones. The latter is in part due to the ability of BTEB1 to influence the numbers of ESR1- and PGR-expressing cells; this was demonstrated here for ST cells, which exhibited differing numbers of PGR (lower)- and ESR1 (higher or lower)-expressing cells in Bteb1(–/–) relative to corresponding WT mice. Interestingly, this activity of BTEB1 appears to be P dependent since in OVX mice injected only with sesame oil or in mice before the P surge, which initiates at 2.5 dpc, the percentage of ESR1- and PGR-expressing cells did not differ with presence or absence of Bteb1. These results suggest the existence of a regulatory loop involving PGR, ESR1, and BTEB1 and highlight the importance of additional studies to carefully investigate this linkage, given its implication in the control of physiological and pathophysiological states regulated by P/PGR in numerous P-target tissues [7, 37].
Several interesting observations reported here provide a framework for mechanistically addressing BTEB1 involvement in PGR/P-dependent processes. The first relates to the ST PGR isoform functionally interacting with BTEB1 to elicit PGR/P inhibition of LE cell proliferation. It has been reported that although both PGR isoforms are expressed in uterine ST, the levels of PGR-A are higher than PGR-B [38]. Since ablation of Pgr-A but not Pgr-B resulted in uterine hyperplasia and severely compromised implantation [21], our findings of aberrant uterine LE proliferation at 3.5 dpc in Bteb1(–/–) mice coincident with decreased PGR expression levels imply a role for BTEB1 in PGR-A-mediated control of LE proliferation. The second relates to the narrow window of peri-implantation (2.5 and 3.5 dpc) at which BTEB1 effects on proliferation, apoptosis, and PGR and ESR1 expression were manifested. After 3.5 dpc, with a few exceptions, we found no major differences in these biological parameters for the two genotypes, suggesting either the loss of the relative importance of BTEB1 postimplantation and/or the expression of other nuclear proteins that can compensate for BTEB1 function at this time [24, 28]. Third, given that PGR has many other coactivators implicated in its transactivity, which include the SRC family of proteins, p300/CBP, and p300/CBP-associated factor [39, 40], it is of interest to determine the cellular context under which BTEB1 is preferentially used by PGR among all other comparably expressed nuclear proteins. Finally, the observation that in OVX mice treated with E + P, absence of BTEB1 resulted in complete refractoriness of GE and ST cells to these steroid hormones (as measured by proliferation index), in contrast to LE cells, which showed sensitivity, albeit blunted, raises questions on the molecular mechanisms underlying cell type-specific regulation of proliferation involving BTEB1. In this regard, it is noteworthy that GE and ST express BTEB1, in contrast to LE, which lacks BTEB1 expression [28]. We suggest that insights from these observations may provide a strategy for ameliorating subinfertility in a cohort of women whose etiology is not dependent on abnormal ovarian function [41, 42].
The normal differentiation of endometrial glands is essential for pregnancy since the timely synthesis and secretion of growth factors and other regulatory proteins by the differentiated GE are requisite for uterine receptivity and other functions of the LE [4, 43]. Although our results also showed that loss of BTEB1 function affected the proliferation, apoptosis, and steroid receptor gene expression in GE to almost the same extent as observed for LE, the mechanisms underlying these changes are likely distinct for each cell type since GE, unlike LE, is a site of BTEB1 expression [28]. Given that GE coexpress BTEB1 and PGR during early pregnancy [44] and that PGR-B is considered to be the predominant PGR isoform involved in endometrial glandular gene and secretory activity [38], further studies to evaluate the consequence of loss of functional PGR-P/ BTEB1 interactions in GE on Bteb1 null mutation could provide insights into the relative paracrine contributions of GE and ST on LE function.
In summary, we have demonstrated that the subfertility phenotype of Bteb1(–/–) mice characterized by lower numbers of implanting embryos [28] may be due in part to alterations in the temporal progression and level of proliferation of endometrial LE cells during peri-implantation, likely leading to developmental asynchrony of the uterine endometrium and the implantation-ready embryo. These alterations, which were manifested within a narrow window of uterine development (2.5–3.5 dpc), are correlated with decreased numbers of PGR-expressing ST cells, suggesting a possible signaling pathway between ST and LE involving BTEB1. Thus, BTEB1 constitutes a novel molecular mediator of endometrial receptivity via its PGR coregulator function. Future studies to mechanistically evaluate the potential regulatory loop linking BTEB1, PGR, and ESR1 as well as to identify the paracrine factors elicited by ST cells in response to BTEB1, acting alone and in concert with PGR/P, will provide interesting insights into the intricate and complex processes essential for uterine receptivity and pregnancy success.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Rosalia C.M. Simmen, University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center, 1120 Marshall St., Little Rock, AR 72202. FAX: 501 364 3161; simmenrosalia{at}uams.edu
Received: 10 March 2005.
First decision: 6 April 2005.
Accepted: 4 May 2005.
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REFERENCES |
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may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. Proc Natl Acad Sci U S A 2002 99:2205-2210This article has been cited by other articles:
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  J M P Pabona, M C Velarde, Z Zeng, F A Simmen, and R C M Simmen Nuclear receptor co-regulator Kruppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus J. Endocrinol., January 1, 2009; 200(1): 63 - 73. [Abstract] [Full Text] [PDF]
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 F. A. Simmen, R. Xiao, M. C. Velarde, R. D. Nicholson, M. T. Bowman, Y. Fujii-Kuriyama, S. P. Oh, and R. C. M. Simmen Dysregulation of intestinal crypt cell proliferation and villus cell migration in mice lacking Kruppel-like factor 9 Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1757 - G1769. [Abstract] [Full Text] [PDF]
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H. Pan, L. Zhu, Y. Deng, and J. W. Pollard Microarray Analysis of Uterine Epithelial Gene Expression during the Implantation Window in the Mouse Endocrinology, October 1, 2006; 147(10): 4904 - 4916. [Abstract] [Full Text] [PDF]
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M. C. Velarde, M. Iruthayanathan, R. R. Eason, D. Zhang, F. A. Simmen, and R. C. M. Simmen Progesterone Receptor Transactivation of the Secretory Leukocyte Protease Inhibitor Gene in Ishikawa Endometrial Epithelial Cells Involves Recruitment of Kruppel-Like Factor 9/Basic Transcription Element Binding Protein-1 Endocrinology, April 1, 2006; 147(4): 1969 - 1978. [Abstract] [Full Text] [PDF]
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