Conditional Ablation of Progesterone Receptor Membrane Component 2 Causes Female Premature Reproductive Senescence

Abstract

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.

Uterine Gα q/11 signaling, in a progesterone‐dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse

“…These PRs are composed of PR membrane component (PGRMC)-1 and PGRMC2, and the G-protein-coupled membrane PRs (56). Although a role for these receptors cannot be ruled out, a major role is not likely based on the PGRMC1-and PGRMC2-KO phenotypes reported in mice (57,58) and the finding that membrane PRs signal via Ga s and Ga i , not Ga q/11 (59). Despite these observations, further studies are required to understand whether these receptors play any role in the Ga q/11 -dependent acquisition of uterine receptivity.…”

Steroids, Pregnancy and Fetal Development

“…These concepts challenge previous notions on processes taking place during pregnancy and invite not only to revisit former data but also to advance in the research of these endocrine-immune mechanisms from this novel perspective. Of note, a number of technical 21Gr fl/fl (9, 10) -Pgrmc1 fl/fl and Pgrmc2 fl/fl (30) tools to discriminate the receptor-specific pathways are to date available ( Table 2) and promise exciting progress in the research in the field.…”

Progesterone receptor membrane component 1 and 2 regulate granulosa cell mitosis and survival through a NFΚB-dependent mechanism†

“…In vitro studies with SIGCs and human granulosa/luteal cells have demonstrated that depletion of either PGRMC1 or PGRMC2 resulted in an inappropriate entry into the cell cycle, which often lead to granulosa cell apoptosis [5,7]. To determine if PGRMC1 could be depleted within the ovary, Pgrmc1/2 fl/fl mice [21] were mated to Amhr2-cre mice [17,22]. This breeding strategy resulted in a 73% reduction in ovarian Pgrmc1 mRNA compared to controls (n = 3/group; P = 0.02).…”