Regulator of G-protein signaling 2 (RGS2) suppresses premature calcium release in mouse eggs

Abstract

During oocyte maturation, capacity and sensitivity of Ca2+ signaling machinery increases dramatically, preparing the metaphase II (MII)-arrested egg for fertilization. Upon sperm-egg fusion, Ca2+ release from IP3-sensitive endoplasmic reticulum stores results in cytoplasmic Ca2+ oscillations that drive egg activation and initiate early embryo development. Premature Ca2+ release can cause parthenogenetic activation prior to fertilization; thus, preventing inappropriate Ca2+ signaling is critical to ensuring robust MII arrest. Here, we show that regulator of G-protein signaling 2 (RGS2) suppresses Ca2+release in MII eggs. Rgs2 mRNA was recruited for translation during oocyte maturation, resulting in ∼20-fold more RGS2 protein in MII eggs compared to fully grown immature oocytes. Rgs2-siRNA-injected oocytes matured to MII; however, they had increased sensitivity to low pH and acetylcholine (ACh), which caused inappropriate Ca2+ release and premature egg activation. When matured in vitro, RGS2-depleted eggs underwent spontaneous Ca2+ increases sufficient to cause premature zona pellucida conversion. Rgs2−/- females had reduced litter sizes and their eggs had increased sensitivity to low pH and ACh. Rgs2−/- eggs also underwent premature zona pellucida conversion in vivo. These findings indicate that RGS2 functions as a brake to suppress premature Ca2+ release in eggs that are poised on the brink of development.