COUP-TFII Regulates Human Endometrial Stromal Genes Involved in Inflammation

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2) is an orphan nuclear receptor involved in cell-fate specification, organogenesis, angiogenesis, and metabolism. Ablation of COUP-TFII in the mouse uterus causes infertility due to defects in embryo attachment and impaired uterine stromal cell decidualization. Although the function of COUP-TFII in uterine decidualization has been described in mice, its role in the human uterus remains unknown. We observed that, as in mice, COUP-TFII is robustly expressed in the endometrial stroma of healthy women, and its expression is reduced in the ectopic lesions of women with endometriosis. To interrogate the role of COUP-TFII in human endometrial function, we used a small interfering RNA-mediated loss of function approach in primary human endometrial stromal cells. Attenuation of COUP-TFII expression did not completely block decidualization; rather it had a selective effect on gene expression. To better elucidate the role of COUP-TFII in endometrial stroma cell biology, the COUP-TFII transcriptome was defined by pairing microarray comparison with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrates that COUP-TFII regulates a subset of genes in endometrial stroma cell decidualization such as those involved in cell adhesion, angiogenesis, and inflammation. Importantly this analysis shows that COUP-TFII plays a role in controlling the expression of inflammatory cytokines. The determination that COUP-TFII plays a role in inflammation may add insight into the role of COUP-TFII in embryo implantation and in endometrial diseases such as endometriosis.

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MiR199a is implicated in embryo implantation by regulating Grb10 in rat

Reproduction ◽

10.1530/rep-13-0290 ◽

2014 ◽

Vol 147 (1) ◽

pp. 91-99 ◽

Cited By ~ 12

Author(s):

Hong-Fei Xia ◽

Jing-Li Cao ◽

Xiao-Hua Jin ◽

Xu Ma

Keyword(s):

Cell Proliferation ◽

Embryo Implantation ◽

Growth Factor Receptor ◽

Inverse Association ◽

Loss Of Function ◽

Endometrial Stromal Cells ◽

Proliferation And Apoptosis ◽

17Β Estradiol

MiR199a was found to be differentially expressed in rat uteri between the prereceptive and receptive phase via microRNA (miRNA) microarray analysis in our previous study. However, the role of miR199a in rat embryo implantation remained unknown. In the study, northern blot results showed that the expression levels of miR199a were higher on gestation days 5 and 6 (g.d.5–6) in rat uteri than on g.d.3–4 and g.d.7–8. In situ localization of miR199a in rat uteri showed that miR199a was mainly localized in the stroma or decidua. The expression of miR199a was not significantly different in the uteri of pseudopregnant rats and evidently increased in the uteri of rats subjected to activation of delayed implantation and experimentally induced decidualization. Treatment with 17β-estradiol or both 17β-estradiol and progesterone significantly diminished miR199a levels. Gain of function of miR199a in endometrial stromal cells isolated from rat uteri inhibited cell proliferation and promoted cell apoptosis. Loss of function of miR199a displayed opposite roles on cell proliferation and apoptosis. Further investigation uncovered a significant inverse association between the expression of miR199a and growth factor receptor-bound protein 10 (Grb10), an imprinted gene, and miR199a could bind to the 3′UTR of Grb10 to inhibit Grb10 translation. In addition, in vivo analysis found that the immunostaining of GRB10 was attenuated in the stroma or decidua from g.d.4 to 6, contrary to the enhancement of miR199a. Collectively, upregulation of miR199a in rat uterus during the receptive phase is regulated by blastocyst activation and uterine decidualization. Enforced miR199a expression suppresses cell proliferation partially through targeting Grb10.

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Inhibition of TMEM16A impedes embryo implantation and decidualization in mice

Reproduction ◽

10.1530/rep-18-0197 ◽

2018 ◽

Cited By ~ 2

Author(s):

Qianrong Qi ◽

Yifan Yang ◽

Kailin Wu ◽

Qingzhen Xie

Keyword(s):

Progesterone Receptor ◽

Stromal Cells ◽

Embryo Implantation ◽

Mouse Uterus ◽

Endometrial Stromal Cells ◽

Uterine Endometrium ◽

Molecule Inhibitor ◽

Pathway Inhibition ◽

And Function ◽

Reproductive Processes

Recent studies revealed that TMEM16A is involved in several reproductive processes, including ovarian estrogen secretion and ovulation, sperm motility and acrosome reaction, fertilization, and myometrium contraction. However, little is known about the expression and function of TMEM16A in embryo implantation and decidualization. In this study, we focused on the expression and regulation of TMEM16A in mouse uterus during early pregnancy. We found that TMEM16A is up-regulated in uterine endometrium in response to embryo implantation and decidualization. Progesterone treatment could induce TMEM16A expression in endometrial stromal cells through progesterone receptor/c-Myc pathway, which is blocked by progesterone receptor antagonist or the inhibitor of c-Myc signaling pathway. Inhibition of TMEM16A by small molecule inhibitor (T16Ainh-A01) resulted in impaired embryo implantation and decidualization in mice. Treatment with either specific siRNA of Tmem16a or T16Ainh-A01 inhibited the decidualization and proliferation of mouse endometrial stromal cells. In conclusion, our results revealed that TMEM16A is involved in embryo implantation and decidualization in mice, compromised function of TMEM16A may lead to impaired embryo implantation and decidualization.

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The Drosophila orphan nuclear receptor seven-up requires the Ras pathway for its function in photoreceptor determination

Development ◽

10.1242/dev.121.1.225 ◽

1995 ◽

Vol 121 (1) ◽

pp. 225-235 ◽

Cited By ~ 3

Author(s):

G. Begemann ◽

A.M. Michon ◽

L. vd Voorn ◽

R. Wepf ◽

M. Mlodzik

Keyword(s):

Cell Fate ◽

Nuclear Receptor ◽

Egf Receptor ◽

Cell Transformation ◽

Orphan Nuclear Receptor ◽

Loss Of Function ◽

Cone Cell ◽

Ras Pathway ◽

Protein Levels ◽

Cone Cells

The Drosophila seven-up (svp) gene specifies outer photoreceptor cell fate in eye development and encodes an orphan nuclear receptor with two isoforms. Transient expression under the sevenless enhancer of either svp isoform leads to a dosage-dependent transformation of cone cells into R7 photoreceptors, and at a lower frequency, R7 cells into outer photoreceptors. To investigate the cellular pathways involved, we have taken advantage of the dosage sensitivity and screened for genes that modify this svp-induced phenotype. We show that an active Ras pathway is essential for the function of both Svp isoforms. Loss-of-function mutations in components of the Ras signal transduction cascade act as dominant suppressors of the cone cell transformation, whilst loss-of-function mutations in negative regulators of Ras-activity act as dominant enhancers. Furthermore, Svp-mediated transformation of cone cells to outer photoreceptors, reminiscent of its wild-type function in specifying R3/4 and R1/6 identity, requires an activated Ras pathway in the same cells, or alternatively dramatic increase in ectopic Svp protein levels. Our results indicate that svp is only fully functional in conjunction with activated Ras. Since we find that mutations in the Egf-receptor are also among the strongest suppressors of svp-mediated cone cell transformation, we propose that the Ras activity in cone cells is due to low level Egfr signaling. Several models that could account for the observed svp regulation by the Ras pathway are discussed.

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PIN-FORMED 1 regulates cell fate at the periphery of the shoot apical meristem

Development ◽

10.1242/dev.127.23.5157 ◽

2000 ◽

Vol 127 (23) ◽

pp. 5157-5165 ◽

Cited By ~ 13

Author(s):

T. Vernoux ◽

J. Kronenberger ◽

O. Grandjean ◽

P. Laufs ◽

J. Traas

Keyword(s):

Cell Fate ◽

Apical Meristem ◽

Transmembrane Protein ◽

Loss Of Function ◽

Hybrid Identity ◽

Hormone Transport ◽

Early Markers ◽

Ideal Tool ◽

And Function

The process of organ positioning has been addressed, using the pin-formed 1 (pin1) mutant as a tool. PIN1 is a transmembrane protein involved in auxin transport in Arabidopsis. Loss of function severely affects organ initiation, and pin1 mutants are characterised by an inflorescence meristem that does not initiate any flowers, resulting in the formation of a naked inflorescence stem. This phenotype, combined with the proposed role of PIN1 in hormone transport, makes the mutant an ideal tool to study organ formation and phyllotaxis, and here we present a detailed analysis of the molecular modifications at the shoot apex caused by the mutation. We show that meristem structure and function are not severely affected in the mutant. Major alterations, however, are observed at the periphery of the pin1 meristem, where organ initiation should occur. Although two very early markers of organ initiation, LEAFY and AINTEGUMENTA, are expressed at the periphery of the mutant meristem, the cells are not recruited into distinct primordia. Instead a ring-like domain expressing those primordium specific genes is observed around the meristem. This ring-like domain also expresses a boundary marker, CUP-SHAPED COTYLEDON 2, involved in organ separation, showing that the zone at the meristem periphery has a hybrid identity. This implies that PIN1 is not only involved in organ outgrowth, but that it is also necessary for organ separation and positioning. A model is presented in which PIN1 and the local distribution of auxin control phyllotaxis.

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Jun mediates Frizzled-induced R3/R4 cell fate distinction and planar polarity determination in the Drosophila eye

Development ◽

10.1242/dev.127.16.3619 ◽

2000 ◽

Vol 127 (16) ◽

pp. 3619-3629 ◽

Cited By ~ 6

Author(s):

U. Weber ◽

N. Paricio ◽

M. Mlodzik

Keyword(s):

Cell Fate ◽

Genetic Interaction ◽

Function Analysis ◽

Loss Of Function ◽

Planar Polarity ◽

Jnk Signaling ◽

Drosophila Eye ◽

Polarity Determination ◽

Signaling Components

Jun acts as a signal-regulated transcription factor in many cellular decisions, ranging from stress response to proliferation control and cell fate induction. Genetic interaction studies have suggested that Jun and JNK signaling are involved in Frizzled (Fz)-mediated planar polarity generation in the Drosophila eye. However, simple loss-of-function analysis of JNK signaling components did not show comparable planar polarity defects. To address the role of Jun and JNK in Fz signaling, we have used a combination of loss- and gain-of-function studies. Like Fz, Jun affects the bias between the R3/R4 photoreceptor pair that is critical for ommatidial polarity establishment. Detailed analysis of jun(−) clones reveals defects in R3 induction and planar polarity determination, whereas gain of Jun function induces the R3 fate and associated polarity phenotypes. We find also that affecting the levels of JNK signaling by either reduction or overexpression leads to planar polarity defects. Similarly, hypomorphic allelic combinations and overexpression of the negative JNK regulator Puckered causes planar polarity eye phenotypes, establishing that JNK acts in planar polarity signaling. The observation that Dl transcription in the early R3/R4 precursor cells is deregulated by Jun or Hep/JNKK activation, reminiscent of the effects seen with Fz overexpression, suggests that Jun is one of the transcription factors that mediates the effects of fz in planar polarity generation.

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The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage

Frontiers in Reproductive Health ◽

10.3389/frph.2021.804921 ◽

2021 ◽

Vol 3 ◽

Author(s):

Joanne Muter ◽

Chow-Seng Kong ◽

Jan J. Brosens

Keyword(s):

Stromal Cells ◽

Acute Stress ◽

Embryo Implantation ◽

Recurrence Risk ◽

Tissue Remodelling ◽

Endometrial Stromal Cells ◽

Decidual Cells ◽

Unk Cells ◽

Acute Stress Response

In each menstrual cycle, the endometrium becomes receptive to embryo implantation while preparing for tissue breakdown and repair. Both pregnancy and menstruation are dependent on spontaneous decidualization of endometrial stromal cells, a progesterone-dependent process that follows rapid, oestrogen-dependent proliferation. During the implantation window, stromal cells mount an acute stress response, which leads to the emergence of functionally distinct decidual subsets, reflecting the level of replication stress incurred during the preceding proliferative phase. Progesterone-dependent, anti-inflammatory decidual cells (DeC) form a robust matrix that accommodates the conceptus whereas pro-inflammatory, progesterone-resistant stressed and senescent decidual cells (senDeC) control tissue remodelling and breakdown. To execute these functions, each decidual subset engages innate immune cells: DeC partner with uterine natural killer (uNK) cells to eliminate senDeC, while senDeC co-opt neutrophils and macrophages to assist with tissue breakdown and repair. Thus, successful transformation of cycling endometrium into the decidua of pregnancy not only requires continuous progesterone signalling but dominance of DeC over senDeC, aided by recruitment and differentiation of circulating NK cells and bone marrow-derived decidual progenitors. We discuss how the frequency of cycles resulting in imbalanced decidual subpopulations may determine the recurrence risk of miscarriage and highlight emerging therapeutic strategies.

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A cohort of Caenorhabditis species lacking the highly conserved let-7 microRNA

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkab022 ◽

2021 ◽

Author(s):

Charles Nelson ◽

Victor Ambros

Keyword(s):

Cell Fate ◽

Nematode Species ◽

Loss Of Function ◽

C Elegans ◽

Adult Transition ◽

Developmental Progression ◽

Caenorhabditis Species ◽

Heterochronic Gene ◽

Bilaterian Animal

Abstract The let-7 gene encodes a highly conserved microRNA with critical functions integral to cell fate specification and developmental progression in diverse animals. In Caenorhabditis elegans, let-7 is a component of the heterochronic (developmental timing) gene regulatory network, and loss-of-function mutations of let-7 result in lethality during the larval to adult transition due to misregulation of the conserved let-7 target, lin-41. To date, no bilaterian animal lacking let-7 has been characterized. In this study, we identify a cohort of nematode species within the genus Caenorhabditis, closely related to C. elegans, that lack the let-7 microRNA, owing to absence of the let-7 gene. Using C. sulstoni as a representative let-7-lacking species to characterize normal larval development in the absence of let-7, we demonstrate that, except for the lack of let-7, the heterochronic gene network is otherwise functionally conserved. We also report that species lacking let-7 contain a group of divergent let-7 paralogs—also known as the let-7-family of microRNAs—that have apparently assumed the role of targeting the lin-41 mRNA.

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β-Catenin (CTNNB1) in the Mouse Uterus During Decidualization and the Potential Role of Two Pathways in Regulating Its Degradation

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.7a7199.2007 ◽

2007 ◽

Vol 55 (9) ◽

pp. 963-974 ◽

Cited By ~ 26

Author(s):

Jennifer L. Herington ◽

JiaJia Bi ◽

John D. Martin ◽

Brent M. Bany

Keyword(s):

Binding Protein ◽

E3 Ligase ◽

Progressive Increase ◽

Pregnant Mouse ◽

Transcriptional Coactivator ◽

Mouse Uterus ◽

Endometrial Stromal Cells ◽

Pregnant Uterus ◽

Steady State Levels

β-catenin plays a role in cell adhesion and as a transcriptional coactivator. Its levels are regulated in cells by controlling its degradation through ubiquitination by two different E3 ligase complexes. One complex contains β-transducing repeat containing (BTRC) protein, which binds to β-catenin when phosphorylated on specific (S33 and S37) residues, whereas the other involves calcyclin-binding protein (CACYBP). The aim of this study was to determine the localization and levels of total and active (S33/S37-dephosphorylated) β-catenin in the pregnant mouse uteri and those undergoing artificially stimulated decidualization. These two forms of β-catenin were localized almost exclusively to the endometrial epithelia just prior to the onset of implantation. Although this localization continued after the onset of implantation, there were less epithelial cells present in areas of the uterus undergoing decidualization. Rather, there was a progressive increase in β-catenin localization in endometrial stromal cells undergoing decidualization in the anti-mesometrial and, to a lesser extent, in the mesometrial regions. The presence of a conceptus was not required for the changes in localization seen in the pregnant uterus because similar findings were also seen in uteri undergoing artificially stimulated decidualization. Finally, overall levels of total, active (S33 and S37 dephosphorylated), and phosphorylated (S33/S37/T42) β-catenin protein and the steady-state levels of calcyclin-binding protein mRNA changed in the uterus during decidualization. The result of this study shows the changing localization and levels of β-catenin in the mouse uterus during decidualization. Further, the results suggest potential roles for both the BTRC and CACYBP E3 ligase mechanisms of β-catenin ubiquitination in the uterus during decidualization.

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Ssc-miR-21-5p regulates endometrial epithelial cell proliferation, apoptosis and migration via the PDCD4/AKT pathway

Journal of Cell Science ◽

10.1242/jcs.248898 ◽

2020 ◽

Vol 133 (23) ◽

pp. jcs248898

Author(s):

Renwu Hua ◽

Xiuling Zhang ◽

Wenchao Li ◽

Weisi Lian ◽

Qiaorui Liu ◽

...

Keyword(s):

Embryo Implantation ◽

Vital Role ◽

Endometrial Receptivity ◽

Akt Pathway ◽

Loss Of Function ◽

Endometrial Epithelial Cell ◽

Programmed Cell Death 4 ◽

And Migration

ABSTRACTEndometrial receptivity plays a vital role in successful embryo implantation in pigs. MicroRNAs (miRNAs), known as regulators of gene expression, have been implicated in the regulation of embryo implantation. However, the role of miRNAs in endometrial receptivity during the pre-implantation period remains elusive. In this study, we report that the expression level of Sus scrofa (ssc)-miR-21-5p in porcine endometrium tissues was significantly increased from day 9 to day 12 of pregnancy. Knockdown of ssc-miR-21-5p inhibited proliferation and migration of endometrial epithelial cells (EECs), and induced their apoptosis. We verified that programmed cell death 4 (PDCD4) was a target gene of ssc-miR-21-5p. Inhibition of PDCD4 rescued the effect of ssc-miR-21-5p repression on EECs. Our results also revealed that knockdown of ssc-miR-21-5p impeded the phosphorylation of AKT (herein referring to AKT1) by targeting PDCD4, which further upregulated the expression of Bax, and downregulated the levels of Bcl2 and Mmp9. Furthermore, loss of function of Mus musculus (mmu)-miR-21-5p in vivo resulted in a decreased number of implanted mouse embryos. Taken together, knockdown of ssc-miR-21-5p hampers endometrial receptivity by modulating the PDCD4/AKT pathway.

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The role of the msh homeobox gene during Drosophila neurogenesis: implication for the dorsoventral specification of the neuroectoderm

Development ◽

10.1242/dev.124.16.3099 ◽

1997 ◽

Vol 124 (16) ◽

pp. 3099-3109 ◽

Cited By ~ 16

Author(s):

T. Isshiki ◽

M. Takeichi ◽

A. Nose

Keyword(s):

Cell Fate ◽

Neural Development ◽

Ectopic Expression ◽

Homeobox Gene ◽

Loss Of Function ◽

Spinal Cord Development ◽

Dorsal Portion ◽

Msx Genes

Development of the Drosophila central nervous system begins with the delamination of neural and glial precursors, called neuroblasts, from the neuroectoderm. An early and important step in the generation of neural diversity is the specification of individual neuroblasts according to their position. In this study, we describe the genetic analysis of the msh gene which is likely to play a role in this process. The msh/Msx genes are one of the most highly conserved families of homeobox genes. During vertebrate spinal cord development, Msx genes (Msx1-3) are regionally expressed in the dorsal portion of the developing neuroectoderm. Similarly in Drosophila, msh is expressed in two longitudinal bands that correspond to the dorsal half of the neuroectoderm, and subsequently in many dorsal neuroblasts and their progeny. We showed that Drosophila msh loss-of-function mutations led to cell fate alterations of neuroblasts formed in the dorsal aspect of the neuroectoderm, including a possible dorsal-to-ventral fate switch. Conversely, ectopic expression of msh in the entire neuroectoderm severely disrupted the proper development of the midline and ventral neuroblasts. The results provide the first in vivo evidence for the role of the msh/Msx genes in neural development, and support the notion that they may perform phylogenetically conserved functions in the dorsoventral patterning of the neuroectoderm.

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