Leukaemia inhibitory factor gene mutations in infertile women

Giess, Ralf; Tanasescu, Irina; Steck, Theodore L.; Sendtner, Michael

doi:10.1093/molehr/5.6.581

Cited by 94 publications

(45 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Intriguingly, gene-targeting experiments revealed that LIF plays an unequivocal role in blastocyst implantation in mice (Stewart et al 1992, Escary et al 1993. LIF is also associated with infertility in humans; reduced uterine concentration of LIF and point mutations of the LIF gene leading to aberrant interaction of LIF with LIFR have been described in infertile women (Laird et al 1997, Giess et al 1999. While the importance of LIF for implantation is well documented, information regarding its receptor utilization and its site of action in heterogeneous uterine cell types during the attachment reaction is limited.…”

Section: Discussionmentioning

confidence: 99%

Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation

Song¹,

Lim²

2006

Reproduction

View full text Add to dashboard Cite

Implantation failure in mice lacking leukemia inhibitory factor (LIF) establishes that this cytokine is crucial to this process. LIF transcripts are expressed in the uterus in a biphasic manner: LIF is expressed in the gland on the morning of day 4 and again in stromal cells surrounding the blastocyst with the onset of implantation in the evening of day 4 of pregnancy. However, it is not yet clear whether both phases of LIF expression are required for implantation, since the receptor usage by uterine LIF still remains elusive. Here we have provided evidence that major cell types expressing theLIF receptor (LIFR) and its signal transducing partner gp130 are mostly disparate in the mouse uterus during the glandular LIF expression in the morning of day 4. In contrast, LIFR and gp130 expressions overlap in the luminal epithelium at the time of blastocyst attachment on the evening of day 4 when the second phase of LIF expression occurs in stromal cells surrounding the blastocyst, suggesting that LIF participates in implantation in a paracrine manner. Similar expression patterns for LIFR and gp130 were observed when a delayed implantation model was used. For example, a transient overlapping expression of LIFR and gp130 was evident at 12 h after estrogen-induced termination of delayed implantation. Co-immunoprecipitation experiments showed that LIFR and gp130 form heterodimers and are available for LIF signaling at the time of blastocyst attachment. We have also shown that an intraperitoneal administration of recombinant LIF in LIF-deficient pregnant mice on the evening of day 4, close to the time when the second phase of LIF expression is normally observed, is sufficient to rescue implantation failure, and that there is no evidence of antagonistic action by soluble forms of the receptors. Collectively, our results have provided evidence that LIFR and gp130 form a functional heterodimer in the uterus during the attachment reaction to direct LIF signaling.

show abstract

Section: Discussionmentioning

confidence: 99%

Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation

Song¹,

Lim²

2006

Reproduction

View full text Add to dashboard Cite

show abstract

“…LIFR and gp130 are expressed in the luminal epithelium at this time, indicating a role for LIF signaling in preparing the human uterus for blastocyst attachment (15). In addition, decreased endometrial LIF production may be a factor in some cases of human infertility (17)(18)(19). An effective LIF antagonist could therefore prevent blastocyst implantation in women.…”

mentioning

confidence: 97%

Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

White¹,

Zhang

Salamonsen³

et al. 2007

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

View full text Add to dashboard Cite

Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expression peaks on day 3.5 of pregnancy (D3.5) (D0.5 ‫؍‬ day of mating plug detection) in the uterine glandular epithelium. LA (7 mg/kg per day) administered from D2.5 to D4.5 via four hourly i.p. injections plus continuous administration via miniosmotic pump resulted in complete implantation failure. To improve its pharmacokinetic properties, we conjugated LA to polyethylene glycol (PEG), achieving a significant increase in serum levels. PEGylated LA (PEGLA) (37.5 mg/kg per day) administered via three i.p. injections between D2.5 and D3.5 also resulted in complete implantation failure. PEGLA immunolocalized to the uterine luminal epithelium at the time of blastocyst implantation. Both LA and PEGLA reduced phosphorylation of the downstream signaling molecule STAT3 in luminal epithelial cells on D3.5. The effects of PEGLA were found to be endometrial, with no embryolethal effects observed. These data demonstrate that administration of a PEGylated LIF antagonist is an effective method of targeting LIF signaling in the endometrium and a promising novel approach in the development of nonhormonal contraceptives for women.embryo implantation ͉ leukemia inhibitory factor ͉ mouse

show abstract

“…At least two polymorphisms in the LIF gene (the rs929271 SNP in the 3'-untranslated region and the Val64Met polymorphism have been shown to be overrepresented in young (< 35 years) women with idiopathic infertility and in sub-fertile young women (signified by a history of fertility treatments other than IVF) [43,91,92]. At the same time, carriership of the variant allele of the rs929271 LIF polymorphism was reported to be associated with increased ongoing pregnancy rates after IVF [93].…”

Section: Reproductive Outcomes and Individual Repair Capacitymentioning

confidence: 99%

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

Petkova¹,

Dimitrova²,

Zhelev³

et al. 2015

Biodiscovery

View full text Add to dashboard Cite

Abbreviations: 8-OH-dG -8-hydroxydeoxyguanosine, AMA -advanced maternal age, AR -assisted reproduction, BER -base excision repair, CDC -US Centre for disease prevention and control, DIC -disseminated intravascular coagulation, DS -Down syndrome, HELLP -haemolysis/elevated liver enzymes/low platelets, ICSI -intracytoplasmic sperm injection, IRC -individual repair capacity, IUGR -intrauterine growth restriction, IUI -intrauterine insemination, IVF -in vitro fertilisation, LIF -leukaemia inhibitory factor, NER -nucleotide excision repair, PCOS -polycystic ovary syndrome, PIH -pregnancy-induced hypertension, ROS -reactive oxygen species, TTD -trichothiodystrophy, w.g. -weeks of gestation, WHO -World Health Organisation, XP -xeroderma pigmentosum. AbstractAt present, childbirth is being progressively postponed until later age. Women aged 35 or older may have to wait longer to conceive than younger women and are more likely to be referred to fertility evaluations, but in a significant proportion a spontaneous conception would be achieved in the timeframe typical of younger women. Pregnancies where mothers are ≥ 35 are associated with more risks for pregnancy loss, chromosomal disease, pregnancy-associated complications, prematurity and low birthweight. These concerns, however, are not uncommon in younger women as well. This puts forward the question whether advanced age per se is the underlying cause for the increased risk for adverse outcomes in older pregnant women, or whether there might be other factors that account for it but do not radically worsen the prospects for favourable outcomes. The individual risks associated with childbirth late in life may stem from maternal genetic background rather than being a simple function of age. There is plenty of preliminary evidence that individual capacity for identification and repair of DNA damage may constitute a major factor in female fertility and fecundity. Subtle deficiencies in the repair capacity may have little to no importance in younger pregnant women but may make a significant difference in older women. The outcomes of pregnancies in women >35 are largely dependent on the prepregnancy health status and the quality of antenatal care, and may not be dramatically different from outcomes in younger women.

show abstract

Leukaemia inhibitory factor gene mutations in infertile women

Cited by 94 publications

References 21 publications

Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation

Evidence for heterodimeric association of leukemia inhibitory factor (LIF) receptor and gp130 in the mouse uterus for LIF signaling during blastocyst implantation

Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

Contact Info

Product

Resources

About