Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation
Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation
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DOI：
10.1073/pnas.151180898
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发表时间：
2001-07-17
影响因子：
11.1
通讯作者：
Stewart, CL
中科院分区：
文献类型：
--
作者：
Cheng, JG;Chen, JR;Stewart, CL
白血病抑制因子(LIF)在子宫中的表达是小鼠胚胎着床所必需的。在这里，我们描述了LIF信号在体内的空间和时间调节，通过使用植入期间不同日期的子宫组织。在此期间，LIF受体主要在子宫腔上皮(LE)表达。分离的上皮细胞对LIF的反应是通过信号转导和转录激活因子(STAT)3的磷酸化和核转位，而不是通过丝裂原激活的蛋白激酶水平的增加。相关的细胞因子II-6、睫状神经营养因子和表皮生长因子不能激活STAT3，尽管表皮生长因子能刺激丝裂原激活的蛋白激酶。在体内，STAT3的激活是由LIF单独诱导的，导致STAT3特异性地定位于LE的核，与子宫容受性的开始相一致。LE对LIF的反应性是暂时调节的，尽管LIF受体在整个植入前阶段存在恒定水平，但Stat的激活被限制在怀孕第4天。因此，子宫容受性受到双重控制，并受LIF在子宫内膜腺中开始表达和LE中受体功能的解除抑制所调节。
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 II-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.