Clark Nicole C, Pru Cindy A, Yee Siu-Pok, Lydon John P, Peluso John J, Pru James K
Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington.
Departments of Cell Biology and Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut.
Endocrinology. 2017 Mar 1;158(3):640-651. doi: 10.1210/en.2016-1701.
The nonclassical progesterone receptors progesterone receptor membrane component (PGRMC) 1 and PGRMC2 have been implicated in regulating cell survival of endometrial and ovarian cells in vitro and are abundantly expressed in these cell types. The objective of this study was to determine if Pgrmc1 and Pgrmc2 are essential for normal female reproduction. To accomplish this objective, Pgrmc1 and/or Pgrmc2 floxed mice (Pgrmc2fl/fl and Pgrmc1/2fl/fl) were crossed with Pgr-cre mice, which resulted in the conditional ablation of Pgrmc1 and/or Pgrmc2 from female reproductive tissues (i.e.,Pgrmc2d/d and Pgrmc1/2d/d mice). A breeding trial revealed that conditional ablation of Pgrmc2 initially led to subfertility, with Pgrmc2d/d female mice producing 47% fewer pups/litter than Pgrmc2fl/fl mice (P = 0.001). Pgrmc2d/d mice subsequently underwent premature reproductive senescence by parities 2 to 5, producing 37.8% fewer litters overall during the trial compared with Pgrmc2fl/fl mice (P = 0.020). Similar results were observed with Pgrmc1/2d/d mice. Based on ovarian morphology and serum P4, the subfertility/infertility was not due to faulty ovulation or luteal insufficiency. Rather an analysis of midgestation implantation sites revealed that postimplantation embryonic death was the major cause of the subfertility/infertility. As with our previous report of Pgrmc1d/d mice, Pgrmc2d/d and Pgrmc1/2d/d mice developed endometrial cysts consistent with accelerated aging of this tissue. Given the timing of postimplantation embryonic demise, uterine decidualization may be disrupted in mice deficient in PGRMC2 or PGRMC1/2. Overall, this study revealed that Pgrmc1 and/or Pgrmc2 are required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan.
非经典孕酮受体孕酮受体膜成分（PGRMC）1和PGRMC2已被证明在体外调节子宫内膜和卵巢细胞的细胞存活，并且在这些细胞类型中大量表达。本研究的目的是确定Pgrmc1和Pgrmc2对正常雌性生殖是否必不可少。为了实现这一目标，将Pgrmc1和/或Pgrmc2基因敲除小鼠（Pgrmc2fl/fl和Pgrmc1/2fl/fl）与Pgr-cre小鼠杂交，导致雌性生殖组织中Pgrmc1和/或Pgrmc2的条件性缺失（即Pgrmc2d/d和Pgrmc1/2d/d小鼠）。一项繁殖试验表明，Pgrmc2的条件性缺失最初导致生育力下降，Pgrmc2d/d雌性小鼠每窝产仔数比Pgrmc2fl/fl小鼠少47%（P = 0.001）。Pgrmc2d/d小鼠随后在第2至5胎时经历了过早的生殖衰老，与Pgrmc2fl/fl小鼠相比，试验期间总体产仔数减少了37.8%（P = 0.020）。Pgrmc1/2d/d小鼠也观察到类似结果。根据卵巢形态和血清P4，生育力下降/不育并非由于排卵异常或黄体功能不全。相反，对妊娠中期着床部位的分析表明，着床后胚胎死亡是生育力下降/不育的主要原因。与我们之前关于Pgrmc1d/d小鼠的报告一样，Pgrmc2d/d和Pgrmc1/2d/d小鼠出现了与该组织加速衰老一致的子宫内膜囊肿。鉴于着床后胚胎死亡的时间，在缺乏PGRMC2或PGRMC1/2的小鼠中，子宫蜕膜化可能会受到破坏。总体而言，本研究表明Pgrmc1和/或Pgrmc2是维持子宫组织结构和正常雌性生殖寿命所必需的。
