scholarly journals Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation

Endocrinology ◽  
2018 ◽  
Vol 159 (6) ◽  
pp. 2459-2472 ◽  
Author(s):  
Yan Yin ◽  
Adam Wang ◽  
Li Feng ◽  
Yu Wang ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Heparan Sulfate ◽  
Signaling Pathways ◽  
Reproductive Tract ◽  
Ovarian Function ◽  
Embryo Implantation ◽  
Uterine Epithelium ◽  
Female Reproductive Tract ◽  
Uterine Receptivity ◽  
Mouse Uterus

Abstract To prepare for embryo implantation, the uterus must undergo a series of reciprocal interactions between the uterine epithelium and the underlying stroma, which are orchestrated by ovarian hormones. During this process, multiple signaling pathways are activated to direct cell proliferation and differentiation, which render the uterus receptive to the implanting blastocysts. One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity by conditionally deleting the N-deacetylase/N-sulfotransferase (NDST) 1 gene (Ndst1) in the mouse uterus using the Pgr-Cre driver, on an Ndst2- and Ndst3-null genetic background. Although development of the female reproductive tract and subsequent ovarian function appear normal in Ndst triple-knockout females, they are infertile due to implantation defects. Embryo attachment appears to occur but the uterine epithelium at the site of implantation persists rather than disintegrates in the mutant. Uterine epithelial cells continued to proliferate past day 4 of pregnancy, accompanied by elevated Fgf2 and Fgf9 expression, whereas uterine stroma failed to undergo decidualization, as evidenced by lack of Bmp2 induction. Despite normal Indian hedgehog expression, transcripts of Ptch1 and Gli1, both components as well as targets of the hedgehog (Hh) pathway, were detected only in the subepithelial stroma, indicating altered Hh signaling in the mutant uterus. Taken together, these data implicate an essential role for HSPGs in modulating signal transduction during mouse implantation.

scholarly journals Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization

2015 ◽  
Vol 112 (49) ◽  
pp. 15166-15171 ◽  
Author(s):  
Shannon D. Whirledge ◽  
Robert H. Oakley ◽  
Page H. Myers ◽  
John P. Lydon ◽  
Francesco DeMayo ◽  
...  
Keyword(s):  
Glucocorticoid Receptors ◽  
Reproductive Tract ◽  
Immune Cell ◽  
Steroid Receptors ◽  
Embryo Implantation ◽  
Female Reproductive Tract ◽  
Mouse Uterus ◽  
Glucocorticoid Signaling ◽  
Endocrine Organs

In addition to the well-characterized role of the sex steroid receptors in fertility and reproduction, organs of the female reproductive tract are also regulated by the hypothalamic–pituitary–adrenal axis. These endocrine organs are sensitive to stress-mediated actions of glucocorticoids, and the mouse uterus contains high levels of the glucocorticoid receptor (GR). Although the presence of GR in the uterus is well established, uterine glucocorticoid signaling has been largely ignored in terms of its reproductive and/or immunomodulatory functions on fertility. To define the direct in vivo function of glucocorticoid signaling in adult uterine physiology, we generated a uterine-specific GR knockout (uterine GR KO) mouse using the PRcre mouse model. The uterine GR KO mice display a profound subfertile phenotype, including a significant delay to first litter and decreased pups per litter. Early defects in pregnancy are evident as reduced blastocyst implantation and subsequent defects in stromal cell decidualization, including decreased proliferation, aberrant apoptosis, and altered gene expression. The deficiency in uterine GR signaling resulted in an exaggerated inflammatory response to induced decidualization, including altered immune cell recruitment. These results demonstrate that GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions.

scholarly journals Mechanisms of fibroblast growth factor signaling in the ovarian follicle

2015 ◽  
Vol 228 (2) ◽  
pp. R31-R43 ◽  
Author(s):  
Christopher A Price
Keyword(s):  
Receptor Binding ◽  
Reproductive Tract ◽  
Ovarian Function ◽  
Ovarian Follicle ◽  
Female Reproductive Tract ◽  
Growth Factor Signaling ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Signaling ◽  
Binding Properties ◽  
Differential Action

Fibroblast growth factors (FGFs) have been shown to alter growth and differentiation of reproductive tissues in a variety of species. Within the female reproductive tract, the effects of FGFs have been focused on the ovary, and the most studied one is FGF2, which stimulates granulosa cell proliferation and decreases differentiation (decreased steroidogenesis). Other FGFs have also been implicated in ovarian function, and this review summarizes the effects of members of two subfamilies on ovarian function; the FGF7 subfamily that also contains FGF10, and the FGF8 subfamily that also contains FGF18. There are data to suggest that FGF8 and FGF18 have distinct actions on granulosa cells, despite their apparent similar receptor binding properties. Studies of non-reproductive developmental biology also indicate that FGF8 is distinct from FGF18, and that FGF7 is also distinct from FGF10 despite similar receptor binding properties. In this review, the potential mechanisms of differential action of FGF7/FGF10 and FGF8/FGF18 during organogenesis will be reviewed and placed in the context of follicle development. A model is proposed in which FGF8 and FGF18 differentially activate receptors depending on the properties of the extracellular matrix in the follicle.

308. FOLLISTATIN SPLICE VARIANTS FST288 AND FST315 INCREASE DURING EARLY MOUSE PREGNANCY: REGULATION BY PROGESTERONE?

2010 ◽  
Vol 22 (9) ◽  
pp. 108
Author(s):  
R. G. Craythorn ◽  
W. R. Winnall ◽  
M. P. Hedger ◽  
P. A. W. Rogers ◽  
D. M. De Kretser ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Early Pregnancy ◽  
Reproductive Tract ◽  
Splice Variants ◽  
Heparan Sulphate ◽  
Activin A ◽  
Female Reproductive Tract ◽  
Mouse Uterus ◽  
Rate Of Increase ◽  
Exogenous Progesterone

Follistatin acts by binding and neutralising the activity of activin-A, which has important regulatory roles in development, reproduction and inflammation. There are two isoforms of follistatin comprising 288 and 315 amino acids (FST288 and FST315), resulting from alternative gene splicing. FST288 binds spontaneously to heparan sulphate and is largely bound to cell surface proteoglycans. FST315 is the predominant circulating form and can only bind to heparan sulphate after binding activin-A. The regulation of these splice variants in the female reproductive tract have not been investigated in detail. In this study, our aim was to quantify the expression of FST288 and FST315 mRNA in the mouse uterus during early pregnancy (days 1–4, pre-implantation), and in response to exogenous oestradiol-17b (100 ng × single s.c. injection, dissection after 24 h) and progesterone (1 mg × three daily s.c. injections, dissection 24 h after last injection) in ovariectomised mice. Gene expression was analysed using quantitative RT-PCR. Primers amplifying a product from exon 5 to 6a (unique to FST288) or from exon 5 to 6b (unique to FST315) were used to discriminate the isoforms. In early pregnancy, expression of both FST288 and FST315 increased significantly (approximately 35-fold and 100-fold, respectively) on days 3–5, relative to days 1–2, corresponding with the increase in circulating progesterone levels that occurs at day 3. A significant increase in FST288 and FST315 mRNA expression (both approximately 35-fold) was also observed in ovariectomised mice in response to exogenous progesterone, but there was no increase in response to oestradiol-17β. In contrast to the similar rate of increase in response to exogenous progesterone, FST315 mRNA expression increased more rapidly than FS288 in early pregnancy, indicating that differential regulation of the two isoforms also occurs. We conclude that progesterone regulates both FST288 and FST315 mRNA expression during early pregnancy in the mouse uterus.

scholarly journals Fibroblast Growth Factor Receptor Two (FGFR2) Regulates Uterine Epithelial Integrity and Fertility in Mice

2014 ◽  
Vol 90 (1) ◽  
Author(s):  
Justyna Filant ◽  
Franco J. DeMayo ◽  
James K. Pru ◽  
John P. Lydon ◽  
Thomas E. Spencer
Keyword(s):  
Reproductive Tract ◽  
Embryo Implantation ◽  
Growth Factor Receptor ◽  
Mutant Mice ◽  
Fibroblast Growth ◽  
Basal Cells ◽  
Normal Numbers ◽  
Mouse Uterus ◽  
Mutant Female ◽  
And Function

Abstract Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate luminal epithelial (LE) cell proliferation in the adult mouse uterus. This study tested the hypothesis that FGFR2 has a biological role in postnatal development and function of the uterus by conditionally deletingFgfr2 after birth using progesterone receptor (Pgr)-Cre mice. AdultFgfr2 mutant female mice were initially subfertile and became infertile with increasing parity. No defects in uterine gland development were observed in conditionalFgfr2 mutant mice. In the adult,Fgfr2 mutant mice possessed a histologically normal reproductive tract with the exception of the uterus. The LE of theFgfr2 mutant uterus was stratified, but no obvious histological differences were observed in the glandular epithelium, stroma, or myometrium. Within the stratified LE, cuboidal basal cells were present and positive for basal cell markers (KRT14 and TRP63). Nulliparous bredFgfr2 mutants contained normal numbers of blastocysts on Day 3.5 postmating, but the number of embryo implantation sites was substantially reduced on Day 5.5 postmating. These results support the idea that loss of FGFR2 in the uterus after birth alters its development, resulting in LE stratification and peri-implantation pregnancy loss.

scholarly journals Patient-derived endometrial organoids from MRKH patients: Insight in disease causing pathways

2021 ◽  
Author(s):  
Sara Y. Brucker ◽  
Thomas Hentrich ◽  
Julia M. Schulze-Hentrich ◽  
Martin Pietzsch ◽  
Noel Wajngarten ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Ovarian Function ◽  
Female Reproductive Tract ◽  
Mrkh Syndrome ◽  
Powerful Research Tool ◽  
Healthy Control ◽  
Organoid Cultures ◽  
Holding Back

The uterus is responsible for the nourishment and mechanical protection of the developing embryo and fetus and is an essential part in mammalian reproduction. The Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. Although heavily studied, the cause of the disease is still enigmatic. Current research in the field of MRKH mainly focusses on DNA-sequencing efforts and, so far, failed to decipher the nature and heterogeneity of the disease, thereby holding back scientific and clinical progress. Here, we developed long-term expandable organoid cultures from endometrium found in uterine rudiment horns of MRKH patients. Phenotypically, they share great similarity with healthy control organoids and are surprisingly fully hormone responsive. Transcriptome analyses, however, identified an array of dysregulated genes that point at potentially disease-causing pathways altered during the development of the female reproductive tract. We consider the endometrial organoid cultures to be a powerful research tool that promise to enable an array of studies into the pathogenic origins of MRKH syndrome and possible treatment opportunities to improve patient quality of life.

scholarly journals Stromal Progesterone Receptors Mediate Induction of Indian Hedgehog (IHH) in Uterine Epithelium and Its Downstream Targets in Uterine Stroma

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3871-3876 ◽  
Author(s):  
Liz Simon ◽  
Kerry A. Spiewak ◽  
Gail C. Ekman ◽  
Jaeyeon Kim ◽  
John P. Lydon ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Embryo Implantation ◽  
Progesterone Receptors ◽  
Uterine Epithelium ◽  
Indian Hedgehog ◽  
Wild Type ◽  
Uterine Receptivity ◽  
Necessary And Sufficient ◽  
Estrogen Stimulation ◽  
Nuclear Receptor Subfamily

Uterine receptivity to embryo implantation depends on appropriate progesterone (P4) and estrogen stimulation. P4 rapidly stimulates production of the morphogen Indian hedgehog (IHH) in murine uterine epithelium as well as downstream molecules in the hedgehog pathway such as Patched homolog 1 (PTCH1) and nuclear receptor subfamily 2, group F, member 2 (NR2F2) in uterine stroma. Studies using IHH-null mice indicate that IHH is obligatory for the normal P4 response in the uterus. To determine whether IHH induction in uterine epithelium is mediated through P4 receptor (PR) in epithelium (E) and/or stroma (S), we produced tissue recombinants using uteri from neonatal PR knockout (ko) mice and wild-type (wt) mice containing PR in S and/or E or lacking PR altogether using a tissue recombinant methodology and assessed their response to P4. In tissue recombinants containing wt-S (wt-S + wt-E and wt-S + ko-E), P4 induced Ihh mRNA expression at 6 h that was 6-fold greater than in oil-treated controls (P < 0.05; n = 6) in both types of tissue recombinants despite the absence of epithelial PR in wt-S + ko-E grafts. Conversely, Ihh mRNA expression was unaffected by P4 in ko-S + ko-E and ko-S + wt-E grafts despite epithelial PR expression in the latter. Nr2f2 and Ptch1 mRNA expression was similar in that it was stimulated by P4 only in recombinants containing stromal PR. These results indicate that stromal PR is both necessary and sufficient for P4 stimulation of epithelial IHH as well as downstream events such as PTCH1 and NR2F2 increases in stroma.

scholarly journals ADAMTS-1: a novel target gene of an estrogen-induced transcription factor, EGR1, critical for embryo implantation in the mouse uterus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mira Park ◽  
So Hee Park ◽  
Hyunsun Park ◽  
Hye-Ryun Kim ◽  
Hyunjung J. Lim ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Gene ◽  
Target Genes ◽  
Expression Profiles ◽  
Embryo Implantation ◽  
Uterine Epithelium ◽  
Expression Vectors ◽  
Dependent Manner ◽  
Mouse Uterus ◽  
Novel Target

Abstract Background Recently, we demonstrated that estrogen (E2) induces early growth response 1 (Egr1) to mediate its actions on the uterine epithelium by controlling progesterone receptor signaling for successful embryo implantation. EGR1 is a transcription factor that regulates the spectrum of target genes in many different tissues, including the uterus. E2-induced EGR1 regulates a set of genes involved in epithelial cell remodeling during embryo implantation in the uterus. However, only few target genes of EGR1 in the uterus have been identified. Result The expression of ADAM metallopeptidase with thrombospondin type 1 motif 1 (Adamts-1) was significantly downregulated in the uteri of E2-treated ovariectomized (OVX) Egr1(−/−) mice. Immunostaining of ADAMTS-1 revealed its exclusive expression in the uterine epithelium of OVX wild-type but not Egr1(−/−) mice treated with E2. The expression profiles of Adamts-1 and Egr1 were similar in the uteri of E2-treated OVX mice at various time points tested. Pre-treatment with ICI 182, 780, a nuclear estrogen receptor (ER) antagonist, effectively inhibited the E2-dependent induction of Egr1 and Adamts-1. Pharmacologic inhibition of E2-induced ERK1/2 or p38 phosphorylation interfered with the induction of EGR1 and ADAMTS-1. Furthermore, ADAMTS-1, as well as EGR1, was induced in stroma cells surrounding the implanting blastocyst during embryo implantation. Transient transfection with EGR1 expression vectors significantly induced the expression of ADAMTS-1. Luciferase activity of the Adamts-1 promoter containing EGR1 binding sites (EBSs) was increased by EGR1 in a dose-dependent manner, suggesting functional regulation of Adamts-1 transcription by EGR1. Site-directed mutagenesis of EBS on the Adamts-1 promoter demonstrated that EGR1 directly binds to the EBS at -1151/-1134 among four putative EBSs. Conclusions Collectively, we have demonstrated that Adamts-1 is a novel target gene of E2-ER-MAPK-EGR1, which is critical for embryo implantation in the mouse uterus during early pregnancy.

scholarly journals New Insights into Development of Female Reproductive Tract—Hedgehog-Signal Response in Wolffian Tissues Directly Contributes to Uterus Development

2021 ◽  
Vol 22 (3) ◽  
pp. 1211
Author(s):  
Ryuma Haraguchi ◽  
Gen Yamada ◽  
Aki Murashima ◽  
Daisuke Matsumaru ◽  
Riko Kitazawa ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Cell Tracking ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Mouse Uterus ◽  
Uterine Growth ◽  
Mullerian Ducts ◽  
Radial Axis ◽  
Hedgehog Signal

The reproductive tract in mammals emerges from two ductal systems during embryogenesis: Wolffian ducts (WDs) and Mullerian ducts (MDs). Most of the female reproductive tract (FRT) including the oviducts, uterine horn and cervix, originate from MDs. It is widely accepted that the formation of MDs depends on the preformed WDs within the urogenital primordia. Here, we found that the WD mesenchyme under the regulation of Hedgehog (Hh) signaling is closely related to the developmental processes of the FRT during embryonic and postnatal periods. Deficiency of Sonic hedgehog (Shh), the only Hh ligand expressed exclusively in WDs, prevents the MD mesenchyme from affecting uterine growth along the radial axis. The in vivo cell tracking approach revealed that after WD regression, distinct cells responding to WD-derived Hh signal continue to exist in the developing FRT and gradually contribute to the formation of various tissues such as smooth muscle, endometrial stroma and vascular vessel, in the mouse uterus. Our study thus provides a novel developmental mechanism of FRT relying on WD.

scholarly journals Dynamic Expression of Interleukin-33 and ST2 in the Mouse Reproductive Tract Is Influenced by Superovulation

2020 ◽  
Vol 68 (4) ◽  
pp. 253-267
Author(s):  
Salma Begum ◽  
Barry E. Perlman ◽  
Nuriban Valero-Pacheco ◽  
Valerie O’Besso ◽  
Tracy Wu ◽  
...  
Keyword(s):  
Estrous Cycle ◽  
Reproductive Tract ◽  
Ovarian Function ◽  
Expression Patterns ◽  
Follicular Development ◽  
Female Reproductive Tract ◽  
Soluble Form ◽  
Vitro Fertilization ◽  
Interleukin 33

Interleukin-33 (IL-33) is an IL-1 family cytokine with pleiotropic effects on diverse cell types. Dysregulated IL-33 signaling has been implicated in pregnancy-related disorders, including preeclampsia and recurrent pregnancy loss, and in ovarian function in women undergoing controlled ovarian stimulation for in vitro fertilization. To date, expression of IL-33 and its receptor subunit, ST2, in the female reproductive tract remains poorly characterized. We identify IL-33-expressing oocytes surrounded by ST2-expressing granulosa cells at all stages of follicular development, in addition to IL-33+ and ST2+ non-endothelial cells in the ovarian stroma and theca layer in ovaries from adult mice. These expression patterns are similar in estrus- and diestrus-stage adults and in pubescent mice, suggesting a role for IL-33 signaling in ovarian function throughout development and in the estrous cycle. In the uterus, we find expression of IL-33 and ST2 in glandular and luminal epithelia during estrus and at the initiation of pregnancy. Uterine IL-33 expression was modulated by the estrous cycle and was reduced in pubescent females. Last, superovulation increases transcripts for IL-33 and the soluble form of ST2 (sST2) in ovaries, and for IL-33 in uteri. Collectively, our findings lay the foundation for studies identifying cell type-specific requirements for IL-33/ST2 signaling in the establishment and maintenance of mouse pregnancy.

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