Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function
Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function
复制标题
DOI：
10.1096/fj.11-193334
复制
发表时间：
2012-03-01
期刊：
影响因子：
4.8
通讯作者：
DeMayo, Francesco J.
中科院分区：
文献类型：
--
作者：
Franco, Heather L.;Rubel, Cory A.;DeMayo, Francesco J.
卵巢类固醇孕酮通过孕酮受体（PR）起作用，协调子宫内膜上皮-间质细胞的通讯，这对其发育和功能至关重要。PR在这些细胞区室中的表达受到严格的时间和内分泌控制。虽然离体研究证明了间质PR表达的重要性，但它们未能显示上皮PR在子宫功能中的作用。在此，使用与Wnt 7a-Cre小鼠杂交的floxed PR（PRf/f）小鼠来定义PR在子宫上皮中的体内作用。在Wnt 7a-Cre（+）PR（f/-）小鼠中，Progestrin不能刺激其上皮靶基因（包括Ihh）的表达。对Ihh进行分析以确定PR是否直接调节上皮基因转录。ChIP-芯片分析鉴定了Ihh的5 '-侧翼区域中的PR结合位点。近端Ihh启动子与PR共转染表明PR直接调节Ihh转录。雌性Wnt 7a-Cre（+）PR（f/-）小鼠由于胚胎附着缺陷、基质细胞蜕膜化和不能停止雌激素诱导的上皮细胞增殖而不育。最后，孕酮不能抑制Wnt 7a-Cre（+）PR（f/-）小鼠的新生子宫内膜腺体发育。因此，上皮PR是调节孕酮上皮靶基因表达以及子宫功能和发育所必需的。Franco，H. L.，鲁贝尔角一、大号M J.，Wetendorf，M.，Fernando-Valdivia，R.郑智W.，Spencer，T. E、贝林格河R.，Lydon，J.P.，DeMayo，F.上皮孕酮受体在子宫发育和功能中发挥多效性作用。FASEB J.26，1218-1227（2012）. www.fasebj.org
The ovarian steroid progesterone, acting through the progesterone receptor (PR), coordinates endometrial epithelial-stromal cell communication, which is critical for its development and function. PR expression in these cellular compartments is under tight temporal and endocrine control. Although ex vivo studies demonstrated the importance of stromal PR expression, they failed to show a role for epithelial PR in uterine function. Here, the in vivo role of PR in the uterine epithelium is defined using floxed PR (PRf/f) mice crossed to Wnt7a-Cre mice. Progesterone was unable to stimulate the expression of its epithelial target genes, including Ihh, in the Wnt7a-Cre(+)PR(f/-) mice. Analysis was conducted on Ihh to determine whether PR directly regulates epithelial gene transcription. ChIP-on-chip analysis identified PR binding sites in the 5'-flanking region of Ihh. Cotransfection of the proximal Ihh promoter with PR demonstrated that PR directly regulates Ihh transcription. Female Wnt7a-Cre(+)PR(f/-) mice are infertile due to defects in embryo attachment, stromal cell decidualization, and the inability to cease estrogen-induced epithelial cell proliferation. Finally, progesterone was unable to inhibit neonatal endometrial glandular development in Wnt7a-Cre(+)PR(f/-) mice. Thus, epithelial PR is necessary for the regulation of progesterone epithelial target gene expression, as well as uterine function and development.-Franco, H. L., Rubel, C. A., Large, M. J., Wetendorf, M., Fernandez-Valdivia, R., Jeong, J.-W., Spencer, T. E., Behringer, R. R., Lydon, J. P., DeMayo, F. J. Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J. 26, 1218-1227 (2012). www.fasebj.org