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Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Francesco J. DeMayo, One Baylor Plaza, Houston, Texas 77030. E-mail: fdemayo{at}bcm.tmc.edu.
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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and -ß, respectively. In the mouse, embryo attachment is followed by a characteristic endometrial transformation, decidualization, which involves both differentiation and cell proliferation. PR action is indispensable (5), whereas estrogen receptor- is not essential (6) for this process. In the mouse, P4 appears to prime the endometrium before embryo attachment/implantation, and thus, it is one of the essential functions regulated by P4 during the periimplantation period. P4 action is mediated by the binding of the steroid to its cognate receptor, the PR. The PR is a member of a family of nuclear receptors, which are transcription factors that regulate gene transcription in response to the binding of the receptor to its specific ligand. The mouse PR consists of two isoforms, PR-A and PR-B. PR-B consists of an additional 160 amino acids on the amino terminus of PR-A (7). The two isoforms are a result of differential usage of two in-frame translation initiation sites. Both isoforms of the murine PR gene have been ablated (5). Furthermore, using site-directed mutagenesis in embryonic stem cells, the PR-A isoform has been specifically ablated (8). These mice have been termed PRKO (PR knockout) and PRAKO (PR-A knockout), respectively. The PRKO mouse demonstrated that PR regulates all aspects of female reproduction. In the uterus, ablation of PR rendered the uterus incapable of undergoing a decidual reaction. When the PRKO mice were placed under chronic estrogen stimulation, increased hyperplasia and an inflammatory response were observed (5). The PRAKO female was also incapable of eliciting a decidual response to steroid stimulation, demonstrating that the PR-A isoform was responsible for the regulation of uterine stroma differentiation during implantation. Therefore, these mice serve as useful tools by which to validate the role of PR in the mouse uterus (9).
Although much is known about the molecular mechanisms of PR action and the physiological role of PR in reproduction, little is known regarding the downstream target genes of PR activation. In an attempt to gain more insights about downstream events of P4/PR action in the endometrium, we initiated medium-density cDNA array screening to identify differentially expressed genes in wild-type and PRKO uterus after acute treatment with P4. This approach allowed the screening of 1200 known genes for their ability to be differentially regulated, specifically by the PR. One of the genes identified as being differentially expressed was Ihh.
Ihh is a member of the developmentally regulated morphogens, the Hedgehog (Hh) gene family (10). The Hh family of proteins was first cloned in Drosophila and has been extensively studied in both Drosophila and higher vertebrates. There are three Hh homologs in mice, namely Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh) (10). In general, Hh signaling regulates both cell proliferation and differentiation by either short-range or long-range actions, as Hh protein is diffusible. This is involved in signaling between two distinct compartments (e.g. epithelium and mesenchyme) (10). The vertebrate Shh acts on a variety of developmental processes including the development of the ventral neural tube, ventral somites (11), left-right asymmetry (12), foregut development (13), polarizing activity of the limb (14), and lung development (15, 16). Dhh is important for spermatogenesis in the testis (17, 18). Ihh has been reported in the regulation of bone development (19, 20), gastrointestinal tract development (21), and embryonic vasculogenesis (22). Regulation of Hh signaling and its function by steroid hormones in the endometrium have not been established previously. Targeted null mutation of Ihh has been made and exhibited perinatal lethality, presumably caused by respiratory failure due to malformation of the thorax (23). Therefore, the role of Ihh in uterine physiology could not be evaluated. In the present study, we have identified Ihh as a downstream target of P4/PR in the uterus. Ihh is acutely induced in luminal epithelium (LE) and glandular epithelium (GE) by P4. Ihh exhibited a dynamic spatio-temporal expression pattern in the uterus during the periimplantation period. Moreover, we demonstrated that the expression pattern of known genes of the Hh signaling pathway are expressed in a similar pattern to Ihh in the pseudopregnant mouse uterus. Our results indicate that uterine Ihh is acutely up-regulated by P4 and the Hh signaling is operable during the periimplantation period, which may exert its function by P4-initiated epithelial-mesenchymal interaction during the periimplantation period.
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RESULTS |
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). Many genes were shown to be differentially expressed. Among these genes, the expression level of Ihh was 6.1-fold lower in PRKO uterine RNA as compared with wild-type uterine RNA. This suggested that ablation of PR function in the presence of P4 affects Ihh mRNA expression. The result of the DNA microarray was validated by ribonuclease (RNase) protection assay (RPA). RPA was performed on uteri from wild-type and PRKO mice (Fig. 1B). RPA demonstrated lower levels of Ihh mRNA in PRKO samples as compared with wild-type samples. These results are consistent with the finding of the DNA microarray.
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). As expected, expression of the PR mRNA was decreased after P4 stimulation.
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, A and B) and immunohistochemical analysis (Fig. 3, C and D) demonstrated that Ihh mRNA and protein were induced in LE and GE of P4-treated wild-type uterus. Treatment with P4 did not induce Ihh protein in PRKO uteri, and in situ hybridization analysis with sense probe or immunohistochemical analysis with nonimmunized serum substituted for primary antibody showed no signal (not shown). Thus, Ihh mRNA and protein were induced by acute treatment with P4 in the epithelial compartment.
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, 3 h after commencement of P4, Ihh mRNA was increased from undetectable levels at 0 h to detectable at 3 h, peaked between 6–9 h, and decreased thereafter. Both amphiregulin and calcitonin induction by P4 could be detected by 6 h, with peak induction of amphiregulin at 6–9 h and calcitonin at 12–15 h. Lactoferrin, an estrogen-responsive gene (30), did not show any induction over this time course (not shown). This analysis demonstrates that Ihh mRNA was rapidly induced by P4. Examination at earlier time courses shows significant induction of Ihh by 2 h (data not shown). In addition, Ihh induction by P4 appeared to precede induction of previously identified P4-responsive genes, amphiregulin and calcitonin.
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). Ihh expression profiles temporarily proceed to the other known P4-regulated implantation markers, such as amphiregulin and calcitonin.
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, A and B). At d 6, immunoreactive PR was down-regulated in the LE and the GE and was mainly detected in periluminal stroma (Fig. 6C). Examination of the expression pattern of Ihh during the periimplantation period by in situ hybridization demonstrated that Ihh was induced in the LE and GE, which was visible at d 2 (Fig. 6D), and strong signals were detected at d 3 (Fig. 6E). At d 6, Ihh expression decreased significantly (Fig. 6F). Thus, Ihh is induced before the implantation window in the pseudopregnant model, and the timing of initial induction in the epithelial cells coincides with the expression of PR in the epithelial cells of the endometrium.
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Ptc-1, a receptor for Hh protein, is induced by Hh signaling. In the uterus, Ptc-1 expression was undetectable at d 2 (Fig. 7A). At d 4, epithelial cells and periepithelial stroma were stained positively (Fig. 7B). At d 6, localized Ptc-1 expression was down-regulated (Fig. 7C), and weak staining was detected in the mesometrial pole of the LE (not shown). Weak HIP-1 staining was shown in the LE and the GE at d 2 (Fig. 7 D), but increased HIP-1 staining was detected in both the LE and periluminal stroma at d 4 (Fig. 7E), and at d 6, became undetectable (Fig. 7F). Similarly, weak staining of COUP-TFII was observed in the LE and periluminal stroma at d 2 (Fig. 8G). At d 4, COUP-TFII mRNA was up-regulated in stromal cells and epithelial cells (Fig. 8 H). At d 6, COUP-TFII expression was down-regulated (Fig. 8I), and localized expression in the mesometrial pole of the LE was observed, which resembles Ptc-1 expression at d 6 (not shown). Thus, Ihh mRNA and its downstream target genes, Ptc-1, HIP-1, and COUP-TFII, are temporarily regulated during the preimplantation period in close association with Ihh expression.
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DISCUSSION |
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The goal of this microarray approach was to detect primary targets of PR activation. To accomplish this goal and avoid the detection of secondary targets of P4 action, an acute treatment of ovariectomized mice with P4 was employed. This study demonstrated a rapid induction of Ihh by P4 similar to, if not sooner than that observed for, amphiregulin and calcitonin (27, 29). This acute induction of Ihh is not due to a nongenomic effect of P4 because it is not induced in PRKO uterus in the presence of P4. Genomic analysis of the sequences flanking the mouse and human Ihh gene identified several putative P4 response elements. However, strict mapping of a transcription start site has yet to be accomplished.
To identify an appropriate cell culture system to investigate the activation of Ihh by P4, two steroid-responsive endometrial carcinoma cell lines, Ishikawa cells (36) and RL95–2 cells (37), were tested for acute P4 stimulation of Ihh expression. Unfortunately, Northern blot and RT-PCR analysis failed to detect any specific signals (data not shown), indicating that these cell lines fail to induce Ihh expression upon P4 treatment. Thus, these cell lines are not appropriate for studying the regulation of Ihh by P4, and precise analysis of 5'-flanking region of Ihh in response to P4 must await mapping of 5'-flanking region and identification of a cell line that mimics the in vivo response. Nonetheless, although our results do not definitively prove that Ihh is a direct target of PR activation, they strongly indicate that Ihh is a promising candidate for the primary response gene of P4/PR. The direct ligand-dependent regulation of Ihh gene transcription by PR still must be demonstrated by systematical in vitro promoter analysis in an appropriate cell line.
Expression of the Ihh Signaling Axis During the Preimplantation Period
We investigated three known downstream target genes of Hh signaling, Ptc-1, HIP-1, and COUP-TFII, during periimplantation. Ptc-1 and HIP-1 belong to the Hh signaling pathway and are induced by Hh (10). Ptc-1 is a receptor for Hh. Therefore, we thought it was necessary to confirm its localization and expression pattern to ascertain whether uterine Ihh is functional. Increased Ihh mRNA at d 3 was followed by Ptc-1 expression in the stromal cells, thus implicating epithelial-mesenchymal interaction. HIP-1 showed a similar pattern of induction. Because HIP-1 negatively regulates Hh signaling (32), its concomitant induction during the periimplantation period might function to ensure precise control of Hh signaling in preimplantation endometrium. Because Ihh is the only member of the Hh family expressed in the mouse uterus (38), this coordinated expression of members of the Hh pathway would indicate regulation of these members by Ihh. Our results of Ihh expression in a pseudopregnant model are consistent with a description in a previous report using timed pregnant mouse uterus (38).
COUP-TFII is a nuclear orphan receptor that belongs to a nuclear hormone receptor superfamily (39). COUP-TFII is highly expressed during embryonic development, and a null mutant exhibited embryonic lethality (
E10) due to defective angiogenesis and inflow tract development (40). There are two highly homologous COUP-TFs, COUP-TFI and II, in mouse and they may play a redundant role (39). In the uterus, COUP-TFII is highly expressed whereas COUP-TFI is undetectable by RPA using specific riboprobes (data not shown). We chose COUP-TFII as an endometrial stromal cell marker for Ihh signaling for the following reasons. First, COUP-TFII is a downstream target gene of Hh signaling in vivo and in vitro. COUP-TFII is highly expressed in motor neurons during development, and ectopic expression of COUP-TFII was induced by transplantation of notochord which secretes Shh (41). The Shh-responsive element within the 5'-flanking region of COUP-TFII had been identified using P19 mouse embryonic carcinoma cells. This element is distinct from the Gli response element and requires protein phosphatase activity (33, 34). Next, the COUP-TFII haploinsufficiency phenotype, caused by a deletion of a single allele of COUP-TFII in mice, demonstrated reduced fecundity in females (40). This phenomena is in part associated with altered uterine functions. COUP-TFII expression and function in the normal endometrium and abnormal endometrium (endometriosis and endometrial cancer) have been reported previously (42, 43, 44, 45, 46). With this in mind, we hypothesized that one of the pathways potentially regulated by Ihh (via PR) might involve COUP-TFII. Concomitant temporal up-regulation of COUP-TFII is consistent with this hypothesis. COUP-TFII is expressed in a variety of adult organs, no cognate ligand has been identified, and null mice are embryonic lethal. Therefore, specific analysis of the uterine functions of COUP-TFII should wait for the development of uterus-specific conditional COUP-TFII mutants.
Potential Role of Ihh Signaling During Periimplantation
A growing number of studies regarding Hh signaling using genetically modified mice indicate that these molecules play essential roles in a variety of physiological processes, not only during development (19, 23, 47, 48, 49). This evidence might allow us to speculate on a potential role of Ihh in the uterus. Physiological functions of Ihh are well studied in bone. In the regulation of bone formation, Ihh signaling promotes cell proliferation and cell differentiation, in part, by coordinating the expression of PTHrP (23, 47, 48), bone morphogenic proteins, BMP2 and 4, noggin, and chordin (19). In the female steroid hormone-responsive tissue, Hh signaling is known to play a role in the mammary gland. Ihh is expressed in mammary gland, and experimental enhancement of Hh signaling in the mammary gland by conditional haploinsufficiency of Ptc-1 resulted in mammary ductal hyperplasia (49). Disruption of the Ihh target, PTHrP, also resulted in disruption of mammary gland development (50, 51). The downstream target genes of Ihh in the bone, such as PTHrP, BMP-2, -4, -5, and -7, and noggin, are all expressed in the uterus (38). Thus, it might be reasonable to speculate that the Ihh signaling axis in the bone and mammary gland is conserved in the uterus and regulates endometrial epithelial and stromal cell proliferation and differentiation. Ihh may also play a role in uterine vascularization during the preimplantation period. It has been demonstrated that Ihh is a primitive endoderm-secreted signal that alone is sufficient to induce formation of hematopoietic and endothelial cells (22). Importantly, ablation of COUP-TFII resulted in early embryonic lethality due, in part, to disruption of angiogenesis (40). Recently, it has been demonstrated also that P4 stimulates angiogenesis in the uterus (52). Although it still remains speculative, one potential role of Ihh is to mediate P4 stimulation of angiogenesis in the uterus through the regulation of the expression of COUP-TFII.
COUP-TFII has been implicated to play a role in mesenchymal-epithelial interaction during organogenesis and angiogenesis (39). Regulation of mesenchymal gene expression such as COUP-TFII by P4-regulated epithelial factor, Ihh, might point to a novel paradigm for the steroid regulation of endometrial function. This epithelial-mesenchymal interaction, acutely initiated by P4 before implantation, had been envisioned. Amphiregulin, which is an epidermal growth factor-like protein, is rapidly induced by P4 in the endometrial epithelial cells, in close association with cessation of epithelial cell proliferation (autocrine) and onset of stromal cell proliferation (paracrine) (29). Consistent with this, PR was localized in the epithelium before the implantation window. Therefore epithelial PR initiates epithelial-mesenchymal interaction, before decidual reaction that is initiated by blastocyst attachment in normal pregnancy (38). Thereafter, PR expression shifts to stromal cells, which undergo decidual transformation (53). Decidualization of the endometrium has been divided into three phases (54). In the first phase, uterine stromal cells are sensitized to a decidualizing stimulus. This sensitization requires P4 treatment (54). The second phase is characterized by induction of stromal cell differentiation. Finally, the third phase consists of maintenance of the growth and development of decidualized cells. Our hypothesis is that P4 induction of epithelium-secreted morphogen regulate both proliferation and differentiation in the mesenchyme. We propose that Ihh is one of the factors induced during the first phase of decidualization, which may act to prime the endometrium for decidualization by regulating the downstream target genes that are required for latter phases of decidualization. Consequently, identification and characterization of the downstream target of Ihh signaling in the uterus are important to validate this hypothesis.
Based on all of the above results, we propose the following working model (Fig. 8
). In this model, P4 induces Ihh in the epithelial cells of endometrium and Ihh signaling into the stromal cells. Induction of the target genes in epithelial cells may also have significant autonomous roles. Ihh-mediated epithelial-mesenchymal interaction might induce downstream genes including COUP-TFII, as well as genes yet to be identified. Such downstream gene products may play a role during the periimplantation period, which involves both cell proliferation, differentiation, and angiogenesis (e.g. decidualization).
Further studies are required to substantiate the physiological significance of Hh signaling. A targeted null mutation of Ihh has been made. However, the Ihh null mutants exhibited short-limbed dwarfism and perinatal lethality, which was presumably caused by respiratory failure due to malformation of the thorax (23). Thus the function of Ihh in other organs, such as uterus, has yet to be defined. Future development of in vivo model systems, such as transgenic mice, to overexpress HIP-1 in epithelial cells to attenuate Hh signaling or conditional knockout of Ihh in the uterus, might be necessary for assessing the role of Ihh signaling in the prereceptive endometrium.
Thus, Ihh is an important factor that regulates a variety of developmental and physiological processes (e.g. in bone, mammary gland, and intestine), and its regulation by P4 in the endometrial epithelial cells might be shedding new light on the P4-regulated endometrial functions through epithelial-mesenchymal interaction before implantation.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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RNA Preparation and RPA
Total RNA was isolated using TRIzol reagent (Life Technologies, Inc., Gaithersburg, MD). Briefly, after the dissection, uteri were cleared from adipose tissues, and were immediately frozen on dry ice and stored at -80 C. Frozen samples were homogenized in TRIzol, and the total RNA was isolated according to the protocol provided by the company.
RPA was performed as described previously (55) using a commercially available kit (RPAII, Ambion, Inc., Austin, TX).
Screening of Differentially Expressed Genes
Total RNA from both wild-type and PRKO uteri were treated with RNase free-deoxyribonuclease to minimize genomic DNA contamination. Subsequently, mRNA was enriched using biotinylated-oligo(dT) and streptoavidin-magnet beads from CLONTECH Laboratories, Inc. Enriched poly A-tailed RNA was isotopically labeled (-32P dATP) by reverse transcription reaction and separated from unincorporated nucleotides using a gel filtration column. The expression array membrane was hybridized with probes for 16 h at 68 C. After a high-stringency wash of the hybridized array, blots were subjected to quantitative analysis by PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA). The specific signals were quantified and fold induction was calculated after normalization using Atlas Vision 3.0 software (CLONTECH Laboratories, Inc.).
Riboprobes
For RPA, 32P-UTP-labeled antisense RNA was synthesized using a commercial in vitro transcription kit (Ambion, Inc.) with linearized template and appropriate RNA polymerase.
For nonisotopic in situ hybridization, digoxigenin-labeled riboprobes were generated using DIG-RNA labeling kit (Roche Diagnostics, Indianapolis, IN).
The cDNA probes for Ihh, HIP-1, were generated by RT-PCR and subcloned into a pCRII-TOPO cloning vector using a kit (Invitrogen, Carlsbad, CA). The sequence of oligonucleotides used to generate cDNA probes are as follows: Ihh, for RPA: forward 5'-CTG TGA ACT GAG CTG ACA AGC GTG-3', reverse 5'-GGG AAT CTA GCA GCA TCG ACT GAG-3', and for in situ hybridization: forward 5'-CCG CGT TGC CAA AAC AAA CG-3', reverse 5'-CCA GGA AAA TAA GCA CAT CA-3'. This probe generated exactly the same result as the probe obtained from Dr. Andrew McMahon (Harvard University, Cambridge, MA). HIP-1, for RPA: forward 5'-GTG GCT CTG GGC TTC TTT GAA GG-3', reverse 5'-GCA CAT TGG ATC TCC TCC AGC AGC-3'. For in situ hybridization forward 5'-CGC CCT TTC GGT TCC TGC TAC TGT C-3', reverse 5'-GCA CAT TGG ATC TCC TCC AGC AGC-3'. Probes for calcitonin and amphiregulin were previously described. Probes for PR was obtained from Dr. Jeff Rosen (Baylor College of Medicine, Houston, TX). Probes for Ptc-1 were from Dr. Matthew P. Scott (Stanford University, Stanford, CA). The cDNA template for cyclophilin was purchased from Ambion, Inc. A probe for COUP-TFII was described previously (40).
Tissue Preparation for Histology
The small portions (5 mm in length) of uteri were fixed in freshly prepared 4% paraformaldehyde in diethyl pyrocarbonate-treated PBS immediately after the dissection for histological evaluation. After overnight fixation at room temperature, tissues were dehydrated through series of ethanol and then processed for paraffin embedding using an automated tissue processor (Shandon Lipshaw, Pittsburgh, PA). Paraffin sections (8 µm) were mounted onto poly-L-lysine-coated slides (VWR Scientific Products, West Chester, PA), and then used for subsequent applications.
Immunohistochemistry
Immunohistochemistry for Ihh was performed by indirect immunoperoxidase staining. After dehydration through graded alcohol, tissue sections were quenched by 3% hydrogen peroxide in absolute methanol for 15 min and then treated with 1x trypsin (Sigma) for 15 min at room temperature, followed by blocking with 10% normal rabbit serum in PBS. The primary antibody against Ihh (goat polyclonal, Research Diagnostics, Flanders, NJ) at 1:200 were incubated on the pretreated sections for 1 h at room temperature in a humidified chamber. Sections were then treated with biotinylated rabbit antigoat IgG (Accurate Chemicals and Scientific Corp., Westbury, NY), and streptoavidin-horseradish peroxidase conjugate (Zymed Laboratories, Inc., South San Francisco, CA) both at 1:1000 dilution, followed by color development using 3,3'-diaminobenzidine as a chromogen. Sections were counterstained with methyl green (Sigma) and mounted with Permount (Fisher Scientific, Pittsburgh, PA).
PR Immunohistochemistory was performed according to the protocol (8) of Dr. John P. Lydon (Baylor College of Medicine).
In Situ Hybridization
Nonisotopic in situ hybridization was conducted by the published protocol from Dr. David Anderson’s laboratory (http://www.muridae.com/wmc/docs/Big_In_Situ.html) with a modification for paraffin sections. Briefly, paraffin sections were dehydrated and fixed with 4% paraformaldehyde. Pretreatment included incubation with 10 mM HCl, acetylation with 0.5% acetic anhydride, and proteinase K treatment. Hybridization (16 h) and high-stringency wash (30 min, twice) was performed at 65 C in the presence of 50% formamide, followed by an extensive wash with 1x SSC (0.15 M sodium chloride; 0.015 M sodium citrate, pH 7.0) at room temperature. After the hybridization, sections were incubated with antidigoxigenin alkaline phosphatase conjugate (1:1000, Roche Diagnostics), and chromogenic detection with nitroblue tetrazolium chloride/5-bromo-4-chloro-3-indolyl phosphate p-toluidine salt (Life Technologies, Inc.) was performed in buffer consisting of 100 mM Tris (pH 9.5), 50 mM MgCl2, 100 mM NaCl. Negative staining was confirmed for all the probes used in this study by sense probe and/or RNaseA-treated sections.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: COUP-TFII, Chicken ovalbumin upsteam promoter-transcription factor II; Dhh, Desert hedgehog; E2, 17ß-estradiol; GE, glandular epithelium; Hh, hedgehog; HIP-1, hedgehog interacting protein 1; Ihh, Indian hedgehog; LE, luminal epithelium; P4, progesterone; PR, progesterone receptor; PRKO, PR knockout; Ptc-1 and -2, patched 1 and 2; RNase, ribonuclease; RPA, ribonuclease protection assay; Shh, Sonic hedgehog.
Received for publication July 20, 2001. Accepted for publication June 14, 2002.
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REFERENCES |
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-deficient mice. Endocrinology 140:2704–2710NURSA Molecule Pages Link:
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 S. K. Dey, H. Lim, S. K. Das, J. Reese, B. C. Paria, T. Daikoku, and H. Wang Molecular Cues to Implantation Endocr. Rev., June 1, 2004; 25(3): 341 - 373. [Abstract] [Full Text] [PDF]
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Y.-P. Cheon, X. Xu, M. K. Bagchi, and I. C. Bagchi Immune-Responsive Gene 1 Is a Novel Target of Progesterone Receptor and Plays a Critical Role during Implantation in the Mouse Endocrinology, December 1, 2003; 144(12): 5623 - 5630. [Abstract] [Full Text] [PDF]
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D. O. Walterhouse, M. L.G. Lamm, E. Villavicencio, and P. M. Iannaccone Emerging Roles for Hedgehog-Patched-Gli Signal Transduction in Reproduction Biol Reprod, July 1, 2003; 69(1): 8 - 14. [Abstract] [Full Text] [PDF]
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