Uterine Epithelial Progesterone Receptor Governs Uterine Receptivity Through Epithelial Cell Differentiation
Uterine Epithelial Progesterone Receptor Governs Uterine Receptivity Through Epithelial Cell Differentiation
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DOI：
10.1210/endocr/bqaa195
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发表时间：
2020-12-01
期刊：
影响因子：
4.8
通讯作者：
Osuga, Yutaka
中科院分区：
文献类型：
--
作者：
Gebril, Mona;Hirota, Yasushi;Osuga, Yutaka
孕激素受体（PGR）是哺乳动物妊娠所必需的。子宫PGR对排卵后卵巢孕酮（P-4）水平升高作出反应，并调节子宫基因转录以实现成功的胚胎植入。虽然上皮和间质P-4-PGR信号可能相互作用，形成适当的子宫内膜环境，子宫容受性和随后的胚胎附着，仍然不清楚上皮P-4-PGR信号在成年子宫中的具体作用。在这里，我们通过将Pgr-floxed和Ltf-Cre小鼠杂交来产生在成年子宫中具有Pgr上皮缺失的小鼠（Pgr（fl/fl）Ltf（Cre）（/+）小鼠）。Pgr（fl/fl）Ltf（Cre）（/+）小鼠由于胚胎附着受损而不育。Pgr（fl/fl）Ltf（Cre）（/+）子宫未表现出上皮生长停滞，表明子宫容受性受损。Pgr（fl/fl）Ltf（Cre）（/+）小鼠在围着床期上皮和间质的P-4反应性基因表达均降低，表明上皮Pgr缺失不仅影响上皮P-4反应性，而且影响间质P-4反应性。此外，子宫LIF，胚胎附着的诱导剂，减少Pgr（fl/fl）Ltf（Cre）（/+）小鼠。使用通过激光捕获显微切割切出的腔上皮标本的RNA-seq分析揭示，与细胞外基质、细胞粘附和细胞增殖相关的信号传导途径在Pgr（fl/fl）Ltf（Cre）（/+）小鼠中改变。这些发现表明，上皮PGR控制上皮和基质P-4反应性和上皮细胞分化，这提供了正常的子宫容受性和随后的胚胎附着。
Progesterone receptor (PGR) is indispensable for pregnancy in mammals. Uterine PGR responds to the heightened levels of ovarian progesterone (P-4) after ovulation and regulates uterine gene transcription for successful embryo implantation. Although epithelial and stromal P-4-PGR signaling may interact with each other to form appropriate endometrial milieu for uterine receptivity and the subsequent embryo attachment, it remains unclear what the specific roles of epithelial P-4-PGR signaling in the adult uterus are. Here we generated mice with epithelial deletion of Pgr in the adult uterus (Pgr(fl/fl)Ltf(Cre)(/+) mice) by crossing Pgr-floxed and Ltf-Cre mice. Pgr(fl/fl)Ltf(Cre)(/+) mice are infertile due to the impairment of embryo attachment. Pgr(fl/fl)Ltf(Cre)(/+) uteri did not exhibit epithelial growth arrest, suggesting compromised uterine receptivity. Both epithelial and stromal expressions of P-4-responsive genes decreased in Pgr(fl/fl)Ltf(Cre)(/+) mice during the peri-implantation period, indicating that epithelial Pgr deletion affects not only epithelial but stromal P-4 responsiveness. In addition, uterine LIF, an inducer of embryo attachment, was decreased Pgr(fl/fl)Ltf(Cre)(/+) mice. The RNA-seq analysis using luminal epithelial specimens dissected out by laser capture microdissection revealed that the signaling pathways related to extracellular matrix, cell adhesion, and cell proliferation are altered in Pgr(fl/fl)Ltf(Cre)(/+) mice. These findings suggest that epithelial PGR controls both epithelial and stromal P-4 responsiveness and epithelial cell differentiation, which provides normal uterine receptivity and subsequent embryo attachment.