Uterine Deletion of Gp130 or Stat3 Shows Implantation Failure with Increased Estrogenic Responses
Uterine Deletion of Gp130 or Stat3 Shows Implantation Failure with Increased Estrogenic Responses
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DOI：
10.1210/me.2013-1086
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发表时间：
2013-09-01
影响因子：
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通讯作者：
Dey, Sudhansu K.
中科院分区：
文献类型：
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作者：
Sun, Xiaofei;Bartos, Amanda;Dey, Sudhansu K.
白血病抑制因子（LIF）是雌激素的下游靶点，对小鼠体内植入至关重要。LIF功能被认为是通过其与LIF受体（LIFR）的结合和辅助受体GP 130（糖蛋白130）的募集介导的，并且该受体复合物然后激活信号转导和转录激活因子（STAT）1/3。然而，LIFR和GP 130通过STAT 3在植入中发挥作用的重要性仍然不确定，因为Lifr、Gp 130或Stat 3的组成性失活显示小鼠的胚胎致死性。为了解决这个问题，我们产生了子宫Gp 130或STAT 3条件性缺失的小鼠，并表明GP 130和STAT 3对子宫容受性和着床至关重要。这些缺失小鼠的着床失败与着床前较高的子宫雌激素反应有关。这些增强的雌激素反应不是由于卵巢激素水平或其核受体表达的变化。在缺失小鼠中，雌激素反应基因乳铁蛋白（Ltf）和粘蛋白1蛋白在子宫中上调。此外，孕酮反应基因，Hoxa 10和印度刺猬（Ihh），在STAT 3失活子宫显着下调。缺失小鼠子宫的这些变化反映在腔上皮分化失败，这是胚泡附着所必需的。
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.