Centre de Recherche en Reproduction et Fertilité, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec, Canada.
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Endocrinology. 2019 Jul 1;160(7):1561-1572. doi: 10.1210/en.2019-00212.
WNT signaling regulates a variety of ovarian processes, including follicle development, granulosa cell (GC) proliferation and differentiation, steroidogenesis, and ovulation. The secreted frizzled-related proteins (SFRPs) comprise a family of WNT signaling antagonists. Sfrp4 expression was previously reported to be induced in ovarian GCs and cumulus cells in vivo following human chorionic gonadotropin treatment, suggesting that it may play key roles in cumulus expansion, ovulation/luteinization, and corpus luteum (CL) function. In this study, we aimed to define the physiological roles of Sfrp4 in the ovary by gene targeting. Sfrp4-null female mice were found to produce larger litters than did their wild-type littermates. Although previous studies had suggested roles of Sfrp4 in luteal cell survival, no differences in CL formation, morphology, steroidogenesis, involution, or luteal cell apoptosis were found in Sfrp4-null mice. Likewise, cumulus expansion occurred normally in Sfrp4-null mice, with minimal changes in cumulus cell gene expression. Hyperfertility in the Sfrp4-null model was ultimately attributed to decreased antral follicle atresia, leading to an enhanced ovulatory rate. Increased expression of FSH- and LH-responsive genes was found in GCs from Sfrp4-null mice, and GCs isolated from Sfrp4-null mice were found to be hyperresponsive to FSH and LH in vitro. Although Sfrp2 was found to be overexpressed in the GCs of Sfrp4-null mice (suggesting a compensatory mechanism), Sfrp2-null mice had normal fertility and ovulatory rates, and Sfrp2/4 double knockout mice did not differ from Sfrp4-null mice. Taken together, our results suggest that SFRP4 acts to attenuate GC responsiveness to gonadotropins, thereby decreasing follicle survival, ovulatory rate, and fertility.
WNT 信号通路调节多种卵巢过程，包括卵泡发育、颗粒细胞（GC）增殖和分化、类固醇生成和排卵。分泌卷曲相关蛋白（SFRPs）构成了 WNT 信号通路拮抗剂家族。先前的研究报道，人绒毛膜促性腺激素处理后，Sfrp4 在卵巢 GC 和卵丘细胞中的表达被诱导，这表明它可能在卵丘扩展、排卵/黄体化和黄体（CL）功能中发挥关键作用。在这项研究中，我们旨在通过基因靶向定义 Sfrp4 在卵巢中的生理作用。发现 Sfrp4 缺失的雌性小鼠比其野生型同窝仔产生更大的窝仔。尽管先前的研究表明 Sfrp4 在黄体细胞存活中的作用，但在 Sfrp4 缺失的小鼠中，CL 的形成、形态、类固醇生成、退化或黄体细胞凋亡没有差异。同样，Sfrp4 缺失的小鼠中卵丘扩展正常，卵丘细胞基因表达变化最小。Sfrp4 缺失模型中的过度生育最终归因于窦前卵泡凋亡减少，导致排卵率增加。在 Sfrp4 缺失的小鼠中，发现 FSH 和 LH 反应基因的表达增加，并且从 Sfrp4 缺失的小鼠中分离的 GC 在体外对 FSH 和 LH 表现出高反应性。尽管发现 Sfrp2 在 Sfrp4 缺失的小鼠的 GC 中过度表达（表明存在补偿机制），但 Sfrp2 缺失的小鼠具有正常的生育力和排卵率，并且 Sfrp2/4 双重缺失的小鼠与 Sfrp4 缺失的小鼠没有差异。总之，我们的结果表明 SFRP4 可减弱 GC 对促性腺激素的反应性，从而降低卵泡存活率、排卵率和生育力。
