Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization
Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization
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DOI：
10.1073/pnas.1508056112
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Shannon D. Whirledge;R. Oakley;P. Myers;J. Lydon;F. DeMayo;J. Cidlowski
中科院分区：
文献类型：
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作者：
Shannon D. Whirledge;R. Oakley;P. Myers;J. Lydon;F. DeMayo;J. Cidlowski
意义糖皮质激素是几个基本过程的主要应激和免疫介质，包括生殖和发育。然而，糖皮质激素信号在子宫中的直接作用在很大程度上是未知的。我们发现小鼠子宫中的糖皮质激素受体（GR）对于正常生育能力至关重要。特别是在子宫中缺乏GR的雌性小鼠由于与子宫内膜基质重塑不足相关的着床缺陷而生育力低下。此外，子宫糖皮质激素信号传导的缺陷导致组织重塑事件期间的异常基因调控。我们的研究结果表明，以前未被认识的功能GR在子宫生理和生育。除了性类固醇受体在生育和生殖中的明确作用外，女性生殖道的器官也受到下丘脑-垂体-肾上腺轴的调节。这些内分泌器官对糖皮质激素的应激介导的作用敏感，小鼠子宫含有高水平的糖皮质激素受体（GR）。虽然GR在子宫中的存在已得到充分证实，但子宫糖皮质激素信号传导在其对生育力的生殖和/或免疫调节功能方面在很大程度上被忽视。为了确定糖皮质激素信号传导在成人子宫生理学中的直接体内功能，我们使用PRcre小鼠模型产生了子宫特异性GR敲除（子宫GR KO）小鼠。子宫GR KO小鼠表现出严重的生育力低下表型，包括第一窝的显著延迟和每窝幼崽减少。妊娠早期缺陷明显表现为胚泡着床减少和随后的基质细胞蜕膜化缺陷，包括增殖减少、异常凋亡和基因表达改变。子宫GR信号传导的缺陷导致对诱导的蜕膜化的过度炎症反应，包括改变免疫细胞募集。这些结果表明，GR是必需的，以建立必要的细胞环境，以维持正常的子宫生物学和生育能力，通过调节子宫特异性的行动。
Significance Glucocorticoids are primary stress and immune mediators of several fundamental processes, including reproduction and development. However, the direct actions of glucocorticoid signaling in the uterus are largely unknown. We have discovered that the glucocorticoid receptor (GR) in the mouse uterus is essential for normal fertility. Female mice lacking GR specifically in the uterus are subfertile due to defects in implantation related to inadequate remodeling of the endometrial stroma. Moreover, the deficiency in uterine glucocorticoid signaling leads to aberrant gene regulation during tissue remodeling events. Our findings demonstrate previously unrecognized functions of GR in both uterine physiology and fertility. In addition to the well-characterized role of the sex steroid receptors in fertility and reproduction, organs of the female reproductive tract are also regulated by the hypothalamic–pituitary–adrenal axis. These endocrine organs are sensitive to stress-mediated actions of glucocorticoids, and the mouse uterus contains high levels of the glucocorticoid receptor (GR). Although the presence of GR in the uterus is well established, uterine glucocorticoid signaling has been largely ignored in terms of its reproductive and/or immunomodulatory functions on fertility. To define the direct in vivo function of glucocorticoid signaling in adult uterine physiology, we generated a uterine-specific GR knockout (uterine GR KO) mouse using the PRcre mouse model. The uterine GR KO mice display a profound subfertile phenotype, including a significant delay to first litter and decreased pups per litter. Early defects in pregnancy are evident as reduced blastocyst implantation and subsequent defects in stromal cell decidualization, including decreased proliferation, aberrant apoptosis, and altered gene expression. The deficiency in uterine GR signaling resulted in an exaggerated inflammatory response to induced decidualization, including altered immune cell recruitment. These results demonstrate that GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions.