The Orphan Nuclear Receptor Nr5a2 Is Essential for Luteinization in the Female Mouse Ovary
The Orphan Nuclear Receptor Nr5a2 Is Essential for Luteinization in the Female Mouse Ovary
复制标题
DOI：
10.1210/en.2013-1765
复制
发表时间：
2014-05-01
期刊：
影响因子：
4.8
通讯作者：
Murphy, Bruce D.
中科院分区：
文献类型：
--
作者：
Bertolin, Kalyne;Gossen, Jan;Murphy, Bruce D.
在卵巢中，卵泡颗粒细胞表达核受体Nr 5a 2（核受体亚家族5 A组成员2），也称为肝受体同源物-1，排卵后，Nr 5a 2表达持续存在于黄体中。先前的研究表明，Nr 5a 2是排卵和黄体类固醇合成所必需的。我们的目的是分析Nr 5a 2在卵巢中的调节作用的时间顺序，重点是其对黄体功能的贡献。我们开发了一种雌性小鼠模型，从窦状卵泡的形成（基因型Nr 5a 2（Cyp 19-/-））的颗粒细胞特异性靶向破坏。在有腔卵泡的颗粒细胞中缺乏Nr 5a 2的小鼠是不育的。虽然它们的卵丘细胞在促性腺激素刺激后经历扩张，但这些小鼠的排卵被破坏，至少部分是由于孕酮受体（Pgr）基因的下调。有腔卵泡中Nr 5a 2的耗竭允许黄体样结构的形成，但不允许功能性黄体的形成，如孕酮水平降低和不能支持假孕激素所证明。Nr 5a 2的消耗尤其是由于胆固醇转运的缺陷而影响孕酮合成，这通过Scarb 1、Ldlr和星星的下调得到证实。该小鼠系与其中Nr 5a 2从初级卵泡向前（基因型Nr 5a 2（Amhr 2-/-））和排卵信号之后（基因型Nr 5a 2（Pgr-/-））耗尽的模型的比较表明，Nr 5a 2在卵泡发育的轨迹上差异性地调节雌性生育力。
In the ovary, the follicular granulosa cells express the nuclear receptor Nr5a2 (nuclear receptor subfamily 5 group A member 2), also known as liver receptor homolog-1, and after ovulation, Nr5a2 expression persists in the corpus luteum. Previous studies demonstrated that Nr5a2 is required for both ovulation and luteal steroid synthesis. Our objectives were to analyze the temporal sequence in the regulatory effects of Nr5a2 in the ovary, with focus on its contribution to luteal function. We developed a female mouse model of granulosa-specific targeted disruption from the formation of the antral follicles forward (genotype Nr5a2(Cyp19-/-)). Mice lacking Nr5a2 in granulosa cells of antral follicles are infertile. Although their cumulus cells undergo expansion after gonadotropin stimulation, ovulation is disrupted in those mice, at least in part, due to the down-regulation of the progesterone receptor (Pgr) gene. The depletion of Nr5a2 in antral follicles permits formation of luteal-like structures but not functional corpora lutea, as evidenced by reduced progesterone levels and failure to support pseudopregnancy. Progesterone synthesis is affected by depletion of Nr5a2 due to, among others, defects in the transport of cholesterol, evidenced by down-regulation of Scarb1, Ldlr, and Star. Comparison of this mouse line with the models in which Nr5a2 is depleted from the primary follicle forward (genotype Nr5a2(Amhr2-/-)) and after the ovulatory signal (genotype Nr5a2(Pgr-/-)) demonstrates that Nr5a2 differentially regulates female fertility across the trajectory of follicular development.