Gene expression profiling of mouse uterine tissue from progesterone receptor-Cre knockout of Dicer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Chad Creighton
PROVIDER: E-GEOD-39181 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Epithelial-stromal interactions in the uterus are required for normal uterine functions such as pregnancy, and multiple signaling pathways are essential for this process. Although Dicer and microRNAs (miRNA) have been implicated in several reproductive processes, the specific role of Dicer and miRNA in uterine development is not known. To address the roles of miRNA in the regulation of these key uterine pathways, we generated a conditional knockout (cKO) of Dicer in the postnatal uterine epithelium and stroma using progesterone receptor (PR)-Cre. These Dicer cKO are sterile with small uteri, which demonstrate significant defects including absence of glandular epithelium and enhanced stromal apoptosis, beginning at postnatal day 15 with expression of Cre and deletion of Dicer. Although these mice had normal serum steroid hormone levels, critical uterine signaling pathways, including progesterone-responsive genes, Indian hedgehog signaling, and the Wnt/Beta-catenin canonical pathway, were dysregulated at the mRNA level.
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Project description:We generated mice with single or double conditional inactivation of SMAD1 and SMAD5 using progesterone receptor (PR) cre (Smad1flox/flox;Smad5flox/flox;Pgr-cre+/-, or “Smad1/5 cKO”). Female mice with single SMAD1 or SMAD5 deletion were subfertile, whereas Smad1/5 cKO were infertile and had no visible implantation sites at 4.5 days post-coitum (dpc), indicating functional redundancy of SMAD1 and SMAD5. Histological and molecular analyses of the Smad1/5 cKO uteri during pregnancy determined that the infertility was the result of impaired uterine receptivity. During the window of implantation, uteri of Smad1/5 cKO mice responded abnormally to estradiol (E2) and to progesterone (P4), retained luminal PR expression, and displayed cytoplasmic FOXO1 mis-localization. Furthermore, uteri of Smad1/5 cKO mice did not respond to an artificial decidual stimulus and the stroma failed to differentiate. To determine the cell surface receptor complex that controls BMP signaling during implantation, we generated mice with conditional deletion of Acvr2a and Acvr2b using Pgr-cre+/-. We determined that Acvr2b cKO females were subfertile, while Acvr2a cKOs were infertile and displayed a range of ovarian and uterine abnormalities, including endometrial and implantation defects that phenocopied those of Smad1/5 cKO mice. Transcriptomic profiling of the Smad1/5 cKO and Acvr2a cKO uterus showed that genes involved in epithelial cell remodeling and microvilli/ciliated cell function were overrepresented in both genotypes. These results demonstrate that BMP signals mediated via ACVR2A and SMAD1/5 control endometrial receptivity and embryo implantation by remodeling the apicobasal polarity of the epithelium during the window of implantation.
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Project description:Implantation of an embryo in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the pregnant uterus, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing uterine-specific Alk2 conditional knockout (cKO) mice. In the absence of ALK2, embryos can invade the uterine epithelium and stroma, but stromal cells cannot undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of C/EBPβ to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (HESC) and discovered that ablation of ALK2 alters HESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing HESC confirmed that BMP signaling protein, SMAD1, directly regulates expression of CEBPB by binding a distinct regulatory sequence in the CEBPB promoter; C/EBPβ, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate embryo implantation in rodents and primates and, for the first time, uncovers a linear pathwayof BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization. gene expression profiling of two groups: control mice and Alk2 cKO mice
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Project description:Implantation of an embryo in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the pregnant uterus, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing uterine-specific Alk2 conditional knockout (cKO) mice. In the absence of ALK2, embryos can invade the uterine epithelium and stroma, but stromal cells cannot undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of C/EBPβ to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (HESC) and discovered that ablation of ALK2 alters HESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing HESC confirmed that BMP signaling protein, SMAD1, directly regulates expression of CEBPB by binding a distinct regulatory sequence in the CEBPB promoter; C/EBPβ, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate embryo implantation in rodents and primates and, for the first time, uncovers a linear pathwayof BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.
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Project description:Bone morphogenetic proteins (BMPs) are transforming growth factor β (TGFβ) family members that regulate the post-implantation and mid-gestation stages of pregnancy. In this study we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. To understand the role of ALK3 in the luminal uterine epithelium, we obtained the gene expression profiles of isolated luminal uterine epithelium from 3.5dpc control and Alk3 cKO mice. Gene expression profiling of isolated luminal uterine epithelium from control and Alk3 cKO mice. two group comparison
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Project description:We have shown that Chrnb4-cre; Dicerflox/flox retinas (Dicer CKO) display a cone dystrophy by postnatal day P21, independent of rod degeneration. To elucidate which miRNAs were involved in such phenotype, miRNA sequencing was performed in whole retinas of P21 and 3.5 month old control and Dicer CKO mice. This experiment aims to identify which miRNAs were differentially expressed in Dicer conditional knockout mice when compared to control mice.
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Project description:Embryo implantation into a receptive endometrium is tightly regulated by a variety of maternal factors, including cytokines, growth factors and transcription factors. Previous studies identified the leukaemia inhibitory factor (LIF), produced in uterine glands, as an essential factor for implantation. It was shown that LIF acts via its cell surface receptor to activate the transcription factor STAT3 in the uterine epithelial cells. However, the mechanisms via which STAT3 promotes uterine receptivity remain unknown. To address the molecular pathways regulated by STAT3 in the uterus, we created mice in which Stat3 gene is conditionally inactivated in uterine epithelium. These mutant mice are infertile due to implantation failure and exhibit a lack of embryo attachment to the luminal epithelium. Gene expression profiling of the epithelial tissue impaired in STAT3 activation revealed dysregulated expression of specific components of junctional complexes, including E-cadherin, M-NM-2-catenin, and claudins, which critically regulate epithelial cell polarity and embryo attachment. Additionally, mice lacking functional epithelial STAT3 showed markedly reduced stromal proliferation and differentiation, indicating that this transcription factor controls stromal function via a paracrine mechanism. The stromal defect arose from a drastic reduction in the production of several members of the epidermal growth factor (EGF) family in luminal epithelium of mutant uteri and consequent lack of activation of EGF receptor signaling and mitotic activity in the stromal cells. Collectively, our results uncovered intricate signaling networks operating downstream of STAT3 in uterine epithelium that regulate epithelial cell polarity, and stromal proliferation and differentiation, which are critical determinants of successful implantation. To identify the downstream targets of STAT3 in mouse uterine epithelial cells during pregnancy, we performed gene expression profling of mouse uterine epithelial cells on day 4 of pregnancy between Stat3 flox control and SW d/d mice. This led to the identification of several junctional molecules (Claudins and Catenins) that are negatively regulated by STAT3 at the time of implantation. Mouse uteirne epithelial cells were isolated from control and knockout mice on the morning of day 4 of pregnancy. (n=3 for each sample), pooled total RNA from these cells was then hybridized to high density affymetrix microarrays according to the Affymetrix protocol (Mouse Genome 430A 2.0 Array) .
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Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.
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Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.
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Project description:Uterine glands and, by inference, their secretions impact uterine receptivity, blastocyst implantation, stromal cell decidualization, and placental development. Changes in gland function across the menstrual cycle are impacted by steroid hormones, estrogen and progesterone, as well as stroma-derived factors. Using an endometrial epithelial organoid (EEO) system, transcriptome and proteome analyses identified distinct responses of the EEO to steroid hormones and prostaglandin E2 (PGE2). Notably, steroid hormones and PGE2 modulated the basolateral secretion of EEO proteins, where cystatin C (CST3) was significantly increased by progesterone and PGE2. CST3 treatment of decidualizing stromal cells significantly decreased the decidualization markers PRL and IGFBP1. The attenuation of stromal cell decidualization via CST3 suggests a role for uterine gland-derived proteins in controlling the extent of decidualization. These findings provide evidence that uterine gland-derived factors directly impact stromal cell decidualization, which has strong implications for better understanding pregnancy establishment and female fertility in humans.
2023-10-11 | PXD034357 | Pride