Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation

Abstract

Leukemia inhibitory factor (LIF) expression in the uterus is essential for embryo implantation in mice. Here we describe the spatial and temporal regulation of LIF signaling in vivo by using tissues isolated from uteri on different days over the implantation period. During this time, LIF receptors are expressed predominantly in the luminal epithelium (LE) of the uterus. Isolated epithelium responds to LIF by phosphorylation and nuclear translocation of signal transducer and activator of transcription (Stat) 3, but not by an increase in mitogen-activated protein kinase levels. The related cytokines Il-6, ciliary neurotrophic factor, as well as epidermal growth factor, do not activate Stat3, although epidermal growth factor stimulates mitogen-activated protein kinase. In vivo Stat3 activation is induced by LIF alone, resulting in the localization of Stat3 specifically to the nuclei of the LE coinciding with the onset of uterine receptivity. The responsiveness of the LE to LIF is regulated temporally, with Stat activation being restricted to day 4 of pregnancy despite the presence of constant levels of LIF receptor throughout the preimplantation period. Uterine receptivity is therefore under dual control and is regulated by both the onset of LIF expression in the endometrial glands and the release from inhibition of receptor function in the LE.

Leukemia inhibitory factor ligand-receptor signaling is important for uterine receptivity and implantation in golden hamsters (Mesocricetus auratus)

“…After the initiation of implantation, however, both Lif-r and gp130, but not their ligand, were expressed in decidual cells surrounding the implanting embryo. This pattern of uterine Lif-r and gp130 localization around the time of implantation was very similar to that reported in the mouse (Cheng et al 2001, Ni et al 2002, human (Cullinan et al 1996), and monkey (Yue et al 2000). The co-localization of Lif-r and gp130 in periimplantation decidual cells suggests that Lif action is important for decidualization.…”

Signal transducer and activator of transcription 3 (Stat3) expression and activation in rat uterus during early pregnancy

“…Nevertheless, embryos homozygous for the gp130 mutation progressively die between 12.5 days postcoitum and term . Furthermore, nuclear localization of Stat3 in day-4 luminal epithelium was not detected in any LIF-deficient mice, indicating that LIF is the principal mediator of Stat3 activation in vivo (Cheng et al 2001).…”

“…In the mouse, Stat3 was localized to the cytoplasm of the luminal epithelium on day 3 of pregnancy. On day 4, Stat3 localization was predominantly to the nuclei of the entire luminal epithelium, and by day 5, Stat3 had relocalized to the cytoplasm in the luminal epithelium (Cheng et al 2001). Because mouse blastocysts implant on the evening of day 4 (2300 -2400 h) (Das et al 1995), it is of value to examine the activation of Stat3 during this time.…”

“…In addition, the activation and nuclear localization of Stat3 in the day-4 luminal epithelium were not detected in any LIF-deficient mice (Cheng et al 2001), indicating that LIF-induced Stat3 activation is important for mouse implantation. Stat3 expression and activation in the mouse uterus during embryo implantation have been examined briefly (Cheng et al 2001). However, the expression, activation and regulation of Stat3 in rat uterus during early pregnancy are still unknown.…”

“…Embryo implantation failed in LIF-deficient mice (Stewart et al 1992). In vivo, Stat3 activation is induced by LIF alone, resulting in the localization of Stat3 specifically to the nuclei of the luminal epithelium on day 4 of pregnancy in mice, coinciding with the onset of uterine receptivity (Cheng et al 2001). In addition, the activation and nuclear localization of Stat3 in the day-4 luminal epithelium were not detected in any LIF-deficient mice (Cheng et al 2001), indicating that LIF-induced Stat3 activation is important for mouse implantation.…”