Kurihara Isao, Lee Dong-Kee, Petit Fabrice G, Jeong Jaewook, Lee Kevin, Lydon John P, DeMayo Francesco J, Tsai Ming-Jer, Tsai Sophia Y
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS Genet. 2007 Jun;3(6):e102. doi: 10.1371/journal.pgen.0030102.
Progesterone and estrogen are critical regulators of uterine receptivity. To facilitate uterine remodeling for embryo attachment, estrogen activity in the uterine epithelia is attenuated by progesterone; however, the molecular mechanism by which this occurs is poorly defined. COUP-TFII (chicken ovalbumin upstream promoter transcription factor II; also known as NR2F2), a member of the nuclear receptor superfamily, is highly expressed in the uterine stroma and its expression is regulated by the progesterone-Indian hedgehog-Patched signaling axis that emanates from the epithelium. To further assess COUP-TFII uterine function, a conditional COUP-TFII knockout mouse was generated. This mutant mouse is infertile due to implantation failure, in which both embryo attachment and uterine decidualization are impaired. Using this animal model, we have identified a novel genetic pathway in which BMP2 lies downstream of COUP-TFII. Epithelial progesterone-induced Indian hedgehog regulates stromal COUP-TFII, which in turn controls BMP2 to allow decidualization to manifest in vivo. Interestingly, enhanced epithelial estrogen activity, which impedes maturation of the receptive uterus, was clearly observed in the absence of stromal-derived COUP-TFII. This finding is consistent with the notion that progesterone exerts its control of implantation through uterine epithelial-stromal cross-talk and reveals that stromal-derived COUP-TFII is an essential mediator of this complex cross-communication pathway. This finding also provides a new signaling paradigm for steroid hormone regulation in female reproductive biology, with attendant implications for furthering our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in such human reproductive disorders as endometriosis and endometrial cancer.
孕酮和雌激素是子宫容受性的关键调节因子。为促进子宫重塑以利于胚胎附着，孕酮会减弱子宫上皮中的雌激素活性；然而，其发生的分子机制尚不清楚。核受体超家族成员COUP-TFII（鸡卵清蛋白上游启动子转录因子II；也称为NR2F2）在子宫基质中高度表达，其表达受源自上皮的孕酮-印度刺猬信号通路- patched信号轴调控。为进一步评估COUP-TFII在子宫中的功能，构建了条件性COUP-TFII基因敲除小鼠。这种突变小鼠因着床失败而不育，胚胎附着和子宫蜕膜化均受损。利用该动物模型，我们发现了一条新的遗传途径，其中BMP2位于COUP-TFII下游。上皮孕酮诱导的印度刺猬调节基质中的COUP-TFII，进而控制BMP2，使蜕膜化在体内得以显现。有趣的是，在缺乏基质来源的COUP-TFII时，明显观察到上皮雌激素活性增强，这阻碍了子宫容受性的成熟。这一发现与孕酮通过子宫上皮-基质相互作用来控制着床的观点一致，并揭示了基质来源的COUP-TFII是这种复杂交叉通讯途径的重要介导因子。这一发现还为女性生殖生物学中类固醇激素调节提供了一种新的信号模式，对进一步理解诸如子宫内膜异位症和子宫内膜癌等人类生殖疾病中激素信号失调的分子机制具有重要意义。
