Progesterone Receptor Membrane Component 1 Mediates Progesterone-Induced Suppression of Oocyte Meiotic Prophase I and Primordial Folliculogenesis.

Meng Guo,Cheng Zhang,Lizhao Feng,Zhenwen Chen,Yuna Li,Zhengpin Wang,Yan Wang,Chao Wang,Xiaoyan Du,Wanbo Niu,Wang Tang

doi:10.1038/srep36869

Abstract

Well-timed progression of primordial folliculogenesis is essential for mammalian female fertility. Progesterone (P4) inhibits primordial follicle formation under physiological conditions; however, P4 receptor that mediates this effect and its underlying mechanisms are unclear. In this study, we used an in vitro organ culture system to show that progesterone receptor membrane component 1 (PGRMC1) mediated P4-induced inhibition of oocyte meiotic prophase I and primordial follicle formation. We found that membrane-impermeable BSA-conjugated P4 inhibited primordial follicle formation similar to that by P4. Interestingly, PGRMC1 and its partner serpine1 mRNA-binding protein 1 were highly expressed in oocytes in perinatal ovaries. Inhibition or RNA interference of PGRMC1 abolished the suppressive effect of P4 on follicle formation. Furthermore, P4-PGRMC1 interaction blocked oocyte meiotic progression and decreased intra-oocyte cyclic AMP (cAMP) levels in perinatal ovaries. cAMP analog dibutyryl cAMP reversed P4–PGRMC1 interaction-induced inhibition of meiotic progression and follicle formation. Thus, our results indicated that PGRMC1 mediated P4-induced suppression of oocyte meiotic progression and primordial folliculogenesis by decreasing intra-oocyte cAMP levels.

Highlights

Several recent studies, including our previous study, showed that progesterone (P4) is critical for regulating primordial follicle formation in several mammalian species
To determine whether membrane P4 receptor or nuclear P4 receptors (nPRs) mediated the effect of P4 on primordial follicle formation, we used BSA-conjugated P4 (P4–BSA), a cell-impermeable form of P4 that does not bind to nPRs
Only 7.6% ± 2.1% oocytes remained in the pachytene stage and 35.8% ± 3.8% oocytes progressed to the dictyate stage in 10 μM dbcAMP plus P4-treated ovaries, which was similar to that observed in vehicle–treated ovaries (Fig. 7B). These results indicated that P4–progesterone receptor membrane component 1 (PGRMC1) interaction inhibited oocyte meiotic progression and primordial follicle formation by decreasing cyclic AMP (cAMP) levels

Summary

Introduction

Several recent studies, including our previous study, showed that progesterone (P4) is critical for regulating primordial follicle formation in several mammalian species. Precipitous decline of high P4 levels and assembly of abundant primordial follicles occur simultaneously after labor[8,9,10]. Of the importance of the quality and quantity of primordial follicles in fertility capacity, it can be suggested that high P4 levels in ovaries act as a physiological inhibitor of folliculogenesis to prevent oocytes from forming premature or abnormal follicles. PGRMC1 mediates the non-genomic effects of P4 on various physiological events such as preventing the apoptosis and proliferation of granulosa/luteal cells, regulating antral follicle development, and inhibiting gonadotropin-releasing hormone (GnRH) neuron activity[19,20]. We used an in vitro fetal ovary culture system to investigate whether PGRMC1 mediated P4-induced inhibition of primordial folliculogenesis and whether this effect involved the modulation of oocyte meiotic progression. We examined whether cyclic AMP (cAMP), a vital messenger molecule that controls oogenesis, was involved in this process

Methods

Results

Conclusion