G protein-coupled estrogen receptor signaling dependent epidermal growth-like factor expression is required for NPR2 inhibition and meiotic resumption in goat oocytes

Abstract

G protein-coupled estrogen receptor (GPER), which is different from traditional estrogen nuclear receptors (ERs), mediates the rapid transduction of nongenomic signals in cells, and works by regulating transcription and intracellular second messengers. Studies have shown that GPER may regulate oocyte maturation, but the relevant mechanism is not entirely clear. Here, goat cumulus-oocyte complexes (COCs) were used as a model to explore the regulation and mechanism of GPER on oocyte maturation. Our study showed that 17β-estradiol (E2) significantly reduced cyclic guanosine monophosphate (cGMP) synthesis in COCs and accelerated the meiotic resumption of goat oocytes via GPER. Further investigation found that GPER mediated the downregulation of natriuretic peptide receptor 2 (NPR2) protein expression in goat cumulus cells by E2. In addition, we found that E2 significantly upregulated the mRNA levels of epidermal growth (EGF)-like factors in goat cumulus cells through GPER, and activated the downstream EGF receptor (EGFR) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. Both AG1478 (EGFR inhibitor) and U0126 (ERK1/2 inhibitor) abolished the inhibitory effect of E2 on the protein expression of NPR2. These results indicate that, through GPER, E2 upregulates the mRNA levels of EGF-like factors in goat cumulus cells and activates the downstream EGF signaling network to suppress the expression of NPR2 protein, which results in a decrease in cGMP synthesis and acceleration of meiotic resumption in goat oocytes.