Implantation Failure in Female Kiss1-/- Mice Is Independent of Their Hypogonadic State and Can Be Partially Rescued by Leukemia Inhibitory Factor
Implantation Failure in Female Kiss1-/- Mice Is Independent of Their Hypogonadic State and Can Be Partially Rescued by Leukemia Inhibitory Factor
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DOI：
10.1210/en.2013-1916
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发表时间：
2014-08-01
期刊：
影响因子：
4.8
通讯作者：
Babwah, Andy V.
中科院分区：
文献类型：
--
作者：
Calder, Michele;Chan, Yee-Ming;Babwah, Andy V.
下丘脑kisspeptin信号系统是生殖神经内分泌轴的主要正向调节因子，小鼠中Kiss1的缺失会导致不育，这种情况通常归因于其促性腺功能低下。我们证明，在Kiss1（-/-）雌性小鼠中，促性腺激素和雌二醇的急性替代可以恢复排卵、交配和受精；然而，这些老鼠仍然无法怀孕，因为胚胎无法植入。黄体酮治疗并没有克服这一缺陷。将Kiss1（-/-）胚胎移植到野生型雌性小鼠体内，可以成功植入，这表明该缺陷是由母体因素引起的。Kisspeptin及其受体在小鼠子宫中表达，我们认为子宫Kisspeptin信号的缺失是着床失败的基础。然而，这种缺失并不妨碍子宫着床腔的闭合，胚胎的正确排列，以及子宫进行脱卵化的能力。相反，Kiss1基因表达的缺失会破坏胚胎对子宫的附着。我们观察到，在着床当天，小鼠着床所必需的细胞因子白血病抑制因子（leukemia inhibitory factor, Lif）在Kiss1（-/-）子宫腺中弱表达，并且外源性Lif给予激素启动的Kiss1（-/-）雌性小鼠足以部分挽救着床。综上所述，我们的研究揭示了子宫kisspeptin信号调节腺体life水平，从而确定了kisspeptin在调节小鼠胚胎着床中的一个新的关键作用。这项研究为探索其他物种，特别是牲畜和人类的这种作用提供了令人信服的理由。
The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(-/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans.