The LIF-Mediated Molecular Signature Regulating Murine Embryo Implantation1

Rosario, Gracy X.; Hondo, Eiichi; Jeong, Jae Wook; Mutalif, Rafidah; Ye, Xiaoqian; Yee, Li Xuan; Stewart, Colin L.

doi:10.1095/biolreprod.114.118513

Cited by 48 publications

(73 citation statements)

References 105 publications

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“…that lack leukemia inhibitory factor (LIF), in which arrest occurs at the attachment stage (Stewart et al, 1992;Fouladi-Nashta et al, 2005;Rosario et al, 2014). LIF is released from uterine glands and diffuses to activate receptors in luminal epithelial cells, leading to Stat3-mediated signalling and a profound shift in gene expression (Rosario et al, 2014). Consistent with this, the defective development of the postnatal gland in E-cadherin (Cdh1)-null, Hoxa11-null and Wnt7a-null mice all result in failure of implantation (Dunlap et al, 2011;Gendron et al, 1997;Reardon et al, 2012).…”

Section: Epithelial Polarity and Gene Expressionmentioning

confidence: 95%

“…Le y appears to have a role in embryo attachment after the clearance of mucin from the glycocalyx , including in the modulation of signalling through the epidermal growth factor receptor (EGFR) and/or mitogen-activated protein kinase (MAPK) pathway . that lack leukemia inhibitory factor (LIF), in which arrest occurs at the attachment stage (Stewart et al, 1992;Fouladi-Nashta et al, 2005;Rosario et al, 2014). LIF is released from uterine glands and diffuses to activate receptors in luminal epithelial cells, leading to Stat3-mediated signalling and a profound shift in gene expression (Rosario et al, 2014).…”

Section: Epithelial Polarity and Gene Expressionmentioning

confidence: 99%

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Embryo–epithelium interactions during implantation at a glance

Aplin

Ruane

2017

Journal of Cell Science

181

140

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At implantation, with the acquisition of a receptive phenotype in the uterine epithelium, an initial tenuous attachment of embryonic trophectoderm initiates reorganisation of epithelial polarity to enable stable embryo attachment and the differentiation of invasive trophoblasts. In this Cell Science at a Glance article, we describe cellular and molecular events during the epithelial phase of implantation in rodent, drawing on morphological studies both in vivo and in vitro, and genetic models. Evidence is emerging for a repertoire of transcription factors downstream of the master steroidal regulators estrogen and progesterone that coordinate alterations in epithelial polarity, delivery of signals to the stroma and epithelial cell death or displacement. We discuss what is known of the cell interactions that occur during implantation, before considering specific adhesion molecules. We compare the rodent data with our much more limited knowledge of the human system, where direct mechanistic evidence is hard to obtain. In the accompanying poster, we represent the embryo-epithelium interactions in humans and laboratory rodents, highlighting similarities and differences, as well as depict some of the key cell biological events that enable interstitial implantation to occur.

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Section: Epithelial Polarity and Gene Expressionmentioning

confidence: 95%

Section: Epithelial Polarity and Gene Expressionmentioning

confidence: 99%

Embryo–epithelium interactions during implantation at a glance

Aplin

Ruane

2017

Journal of Cell Science

181

140

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“…Expression of Lif induction in the uterine glands requires ESR1 (45), and ChIP-seq analysis of the mouse uterus revealed ESR1 binding to the coding and 3′ UTR regions of the Lif gene (46). However, the Lif gene and its upstream promoter-enhancer region are not bound by FOXA2 in available Chip-seq analyses of the mouse uterus (18,39). Indeed, FOXA1 renders ESR1 functional in breast cancer cells by mediating ESR1 binding and transcriptional activity and maintaining chromatin structure and accessibility (42,47).…”

Section: On Gd 35 Induces the Expression Of Lif In The Glands Of Thementioning

confidence: 99%

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Kelleher

Wang

Pru

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

122

177

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Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.T he uterus is comprised of two tissue compartments, the endometrium and the myometrium. The endometrium contains three cell types, luminal epithelium (LE), glandular epithelium (GE), and stroma. In mice, the uterus becomes receptive to blastocyst implantation on gestational day (GD) 4 (with the observation of a postcoital vaginal plug designated GD 0.5); it is prereceptive on GD 1-3, and by the afternoon of GD 5 it becomes nonreceptive (refractory) (1-3). Dynamic changes in ovarian estrogen and progesterone production act via the uterus to regulate uterine receptivity, blastocyst implantation, and stromal cell decidualization necessary for the establishment of pregnancy (4-6). The implantation process, which is initiated by the attachment of the blastocyst trophectoderm to the receptive LE, occurs before or right after midnight in the evening of GD 4 and becomes more prominent by the morning of GD 5. By GD 6, the trophectoderm begins to contact directly stromal cells that then begin to differentiate into decidual cells, which are required for successful pregnancy because they regulate placental development and local maternal immune responses (7,8).The infertility observed in leukemia inhibitory factor (Lif)-null mice and uterine gland-knockout (UGKO) mice and sheep established ...

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“…Reduced IGF1R expression has been reported in mid-secretory endometrium in women with unexplained infertility (Wu and Zhou, 2004). There is evidence for regulation by leukemia inhibitory factor (LIF), which is required for endometrial receptivity in mice (Rosario et al, 2014). miR-145 in endometrium might be sensitive to steroid hormone -whereas estrogen influences expression in mouse splenic lymphocytes (Dai et al, 2008), it is under the control of progesterone in murine endometrial epithelial cells (Yuan et al, 2014).…”

Section: Research Articlementioning

confidence: 99%

miR-145 suppresses embryo–epithelial juxtacrine communication at implantation by modulating maternal IGF1R

Kang¹,

Lees²,

Matthews³

et al. 2015

Development

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Successful implantation requires the synchronization of viable embryonic development with endometrial receptivity. The mechanisms allowing for the initiation of crosstalk between the embryo and the endometrium remain elusive; however, recent studies have revealed that there are alterations in endometrial microRNAs (miRs) in women suffering repeated implantation failure and that one of the altered miRs is miR-145. We assessed the role of miR-145 and its target IGF1R, in early implantation. miR-145 overexpression and IGF1R knockdown were achieved in Ishikawa endometrial cells. Quantitative PCR, western blotting and 39UTR luciferase reporter assays confirmed that IGF1R is a direct target of miR-145 in the endometrium. Attachment of mouse embryos or IGF1-coated beads to endometrial epithelial cells was used to study the effects of altered miR-145 and/or IGF1R expression on early implantation events. miR-145 overexpression or specific reduction of IGF1R impaired attachment in both cases. An IGF1R target protector prevented the miR-145-mediated reduction in IGF1R and reversed the effect of miR-145 overexpression on attachment. The data demonstrate that miR-145 influences embryo attachment by reducing the level of IGF1R in endometrium.

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The LIF-Mediated Molecular Signature Regulating Murine Embryo Implantation1

Cited by 48 publications

References 105 publications

Embryo–epithelium interactions during implantation at a glance

Embryo–epithelium interactions during implantation at a glance

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

miR-145 suppresses embryo–epithelial juxtacrine communication at implantation by modulating maternal IGF1R

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