Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice

Fouladi-Nashta, Ali A.; Jones, Carolyn J.P.; Nijjar, N.; Mohamet, Lisa; Smith, Austin; Chambers, Ian; Kimber, Susan J.

doi:10.1016/j.ydbio.2005.01.033

Cited by 88 publications

(87 citation statements)

References 85 publications

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“…Apposition has not been observed in vivo in humans (Hertig et al 1959) or other primates (Enders 2000), probably because interactions between the embryo and epithelium are highly tenuous and embryos are lost during processing for histology. In mice, the uterus closes over the embryo to create an implantation chamber wherein apposition stages can be found by serial sectioning (Enders & Schlafke 1969, Fouladi-Nashta et al 2005. Here, the outer trophectodermal surface closely approaches the apical uterine epithelium.…”

Section: Discussionmentioning

confidence: 99%

Early stages of implantation as revealed by an in vitro model

Singh¹,

Nardo²,

Kimber³

et al. 2010

Reproduction

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Our limited understanding of the processes underlying steroid hormonal control of human endometrial receptivity is largely due to the lack of a relevant model system. To overcome scarcity of material, we have developed a model in which mouse embryos attach to human Ishikawa cells, which express functional steroid hormone receptors. Blastocysts flushed from day 4 pregnant superovulated mice were transferred to confluent Ishikawa cell monolayers. After 48 h of co-culture, 85% of the blastocysts had attached loosely, but only 40% attached stably to the epithelial cell surface. In contrast, 95% of the embryos attached stably to tissue culture plastic. Thus, weak attachment of a majority of the embryos was followed by stronger adhesion of a smaller proportion. Seventeen percent of the transferred blastocysts modified the epithelial cell surface with loss of MUC1 at the attachment site, extending variably to adjacent epithelial cells. Initially, stable attachment occurred without disruption to the integrity of the epithelial monolayer, but at later stages after the embryo had spread laterally, displacement of subjacent cells was observed. A modest increase in stable attachment, but no changes to MUC1 clearance, was observed after assisted hatching. After 24 h priming of Ishikawa cells by 17b-oestradiol (OE 2 ) followed by 72-h incubation with medroxyprogesterone acetate and OE 2 , stable attachment increased from 40 to 70%. Initial attachment is efficient either in the presence or in the absence of hormone; steroid treatment increased the incidence of stable attachment. Implantation failure is predicted to occur in this model when embryos fail to progress from initial to stable attachment.

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Section: Discussionmentioning

confidence: 99%

Early stages of implantation as revealed by an in vitro model

Singh¹,

Nardo²,

Kimber³

et al. 2010

Reproduction

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“…The H-type-1 antigen is associated with implantation and is misregulated in the Lif null uterus at the expected time of implantation (Fouladi-Nashta et al 2005). On day 5 of pregnancy, no H-type-1 antigen was detected in the LE at the site of implantation in control uteri and it (A and B) On day 5 of pregnancy, implantation sites were visualised by i.v.…”

Section: H-type-1 Antigen Expressionmentioning

confidence: 99%

“…First, on day 1 of pregnancy LIF expression is stimulated by ovulatory oestrogen in both luminal and glandular epithelium. Second, on day 4 nidatory oestrogen stimulates expression of both Lif mRNA and protein in the glandular epithelium (Bhatt et al 1991, Stewart et al 1992, Fouladi-Nashta et al 2005. This peak of LIF expression is essential for embryo implantation into the uterus on the evening of day 4 of pregnancy (Chen et al 2000).…”

Section: Introductionmentioning

confidence: 99%

“…The first insight into the crucial role of LIF in murine implantation came with the generation of mice with a null mutation of the gene encoding Lif. These mice were infertile because of the failure of blastocyst implantation (Stewart et al 1992, Escary et al 1993, Fouladi-Nashta et al 2005. The importance of LIF for successful embryo implantation in the mouse may be of general significance to all mammals, as increased levels of LIF during pregnancy have been shown to be conserved.…”

Section: Introductionmentioning

confidence: 99%

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Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Mohamet

Heath²,

Kimber³

2009

Reproduction

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Uteri of Lif null mice do not support embryo implantation. Since deletion of some genes often prevents the survival of null mice to adulthood, we have used a proven inhibitor of leukaemia inhibitory factor (LIF) signalling to identify the precise window of time during which LIF is required in vivo, and assessed the cellular expression of several LIF-associated targets. On day 4 of pregnancy, mice were injected with hLIF-05 (inhibitor) into the uterine lumen, with corresponding volumes of PBS (vehicle) injected into the contralateral horn. On days 5 and 6, the number of implantation sites was recorded and the uteri processed for immunohistochemistry. Blockade of LIF on day 4 reduced embryo implantation by 50% (P%0.0001) and was effective maximally between 0930 and 1230 h. Antagonism of LIF signalling was evidenced by a lack of phosphorylated STAT3 in the luminal epithelium (LE). Amphiregulin was absent from the LE on day 4 evening and H-type-1 antigen expression was retained in the LE on day 5 in inhibited uteri. Interleukin-1a and oncostatin M expression were reduced in the stroma on day 6, following LIF inhibition. Unexpectedly, PTGS2 expression in stroma was unaffected by LIF inhibition in vivo, in contrast to Lif null mice. In summary, this suggests that LIF signalling is effective for implantation during a discrete time window on day 4 and antagonism of LIF signalling recapitulates many features exhibited in Lif null uteri. The data presented validates the use of antagonists to investigate tissue specific and temporal cytokine signalling in reproductive function.

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“…The uteri of aglandular Foxa2-deleted (Pgr Cre/+ Foxa2 f/f ) mice lacked Lif, which is a gland-derived implantation factor induced by estrogen from the ovary on GD 4 (24,25) and also is expressed in the subluminal stroma at the implantation site on GD 5 (26). LIF is critical for embryo implantation (15,25) and has pleiotropic effects on the LE and stroma to regulate uterine receptivity and perhaps stromal cell decidualization (24,27).…”

mentioning

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.

126

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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Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice

Cited by 88 publications

References 85 publications

Early stages of implantation as revealed by an in vitro model

Early stages of implantation as revealed by an in vitro model

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

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

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