Uterine Deletion ofGp130orStat3Shows Implantation Failure with Increased Estrogenic Responses

Abstract

Leukemia inhibitory factor (LIF), a downstream target of estrogen, is essential for implantation in mice. LIF function is thought to be mediated by its binding to LIF receptor (LIFR) and recruitment of coreceptor GP130 (glycoprotein 130), and this receptor complex then activates signal transducer and activator of transcription (STAT)1/3. However, the importance of LIFR and GP130 acting via STAT3 in implantation remains uncertain, because constitutive inactivation of Lifr, Gp130, or Stat3 shows embryonic lethality in mice. To address this issue, we generated mice with conditional deletion of uterine Gp130 or Stat3 and show that both GP130 and STAT3 are critical for uterine receptivity and implantation. Implantation failure in these deleted mice is associated with higher uterine estrogenic responses prior to the time of implantation. These heightened estrogenic responses are not due to changes in ovarian hormone levels or expression of their nuclear receptors. In the deleted mice, estrogen-responsive gene, Lactoferrin (Ltf), and Mucin 1 protein, were up-regulated in the uterus. In addition, progesterone-responsive genes, Hoxa10 and Indian hedgehog (Ihh), were markedly down-regulated in STAT3-inactivated uteri. These changes in uteri of deleted mice were reflected by the failure of differentiation of the luminal epithelium, which is essential for blastocyst attachment.

Egr1 Protein Acts Downstream of Estrogen-Leukemia Inhibitory Factor (LIF)-STAT3 Pathway and Plays a Role during Implantation through Targeting Wnt4

“…The stromal localization of LIF is similar to phosphorylated STAT3 expression pattern (10). Conditional knock-out or transient suppression of STAT3 results in implantation failure, which suggests the critical role of STAT3 during implantation (11)(12)(13)(14). As a pleiotropic cytokine, LIF is also essential for mouse and human decidualization (15,16).…”

Molecular determinants of uterine receptivity

“…This signaling pathway, including Stat3 nuclear translocation in the luminal and glandular epithelium, is attenuated in LIF null mutant uteri (Cheng et al, 2001). Recent studies further demonstrate that uterine conditional deletion of Stat3 also induces implantation failure (Lee et al, 2013, Pawar et al, 2013, Sun et al, 2013. In the human, a low level of LIF is associated with unexplained recurrent abortion and infertility (Hambartsoumian, 1998, Piccinni et al, 1998.…”

Assessment of Embryo-Induced Transcriptomic Changes in Hamster Uterus Using RNA-Seq

“…Recently, niclosamide has emerged in anti-cancer therapeutics for various types of cancer [48, 49]. One direct target for niclosamide is the signal transducer and activator of transcription 3 (STAT3) [50], which is crucial for embryo implantation [51-53]. Quinostatin was identified as a mTOR inhibitor through a high-throughput and cell-based assay [54].…”