Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte

Abstract

Mammalian oocytes are arrested in meiotic prophase by an inhibitory signal from the surrounding somatic cells in the ovarian follicle. In response to luteinizing hormone (LH), which binds to receptors on the somatic cells, the oocyte proceeds to second metaphase, where it can be fertilized. Here we investigate how the somatic cells regulate the prophase-to-metaphase transition in the oocyte, and show that the inhibitory signal from the somatic cells is cGMP. Using FRET-based cyclic nucleotide sensors in follicleenclosed mouse oocytes, we find that cGMP passes through gap junctions into the oocyte, where it inhibits the hydrolysis of cAMP by the phosphodiesterase PDE3A. This inhibition maintains a high concentration of cAMP and thus blocks meiotic progression. LH reverses the inhibitory signal by lowering cGMP levels in the somatic cells (from ~2 μM to ~80 nM at 1 hour after LH stimulation) and by closing gap junctions between the somatic cells. The resulting decrease in oocyte cGMP (from ~1 μM to ~40 nM) relieves the inhibition of PDE3A, increasing its activity by ~5-fold. This causes a decrease in oocyte cAMP (from ~700 nM to ~140 nM), leading to the resumption of meiosis.

Regulation of sheep oocyte maturation using cAMP modulators

“…A high intra-oocyte cAMP concentration is produced endogenously within the oocyte by adenylate cyclases and constitutively active G-protein-coupled receptors (GPR) [2] and is generated by cumulus cells (CC) and transported to the oocyte via gap junctions [3,4]. Cyclic guanosine monophosphate (cGMP) diffuses from granulosa cells to the oocyte and inhibits cAMP degradation by inhibiting PDE3A [5,6]. In rodents, elevated cAMP concentrations activate protein kinase-A (PKA), followed by complex inhibitory mechanisms involving CDK1 -cyclin B kinase proteins suppressing activation of maturation promoting factor (MPF) and preventing meiosis [7][8][9].…”

“…In rodents, elevated cAMP concentrations activate protein kinase-A (PKA), followed by complex inhibitory mechanisms involving CDK1 -cyclin B kinase proteins suppressing activation of maturation promoting factor (MPF) and preventing meiosis [7][8][9]. In vivo, the pre-ovulatory surge of LH decreases cGMP concentrations in granulosa cells as well as oocytes [5,6]; the subsequent activation of PDE3A resulted in degradation of cAMP, activation of MPF, and resumption of meiosis (review; Conti et. al.…”

Pioneering the Xenopus Oocyte and Egg Extract System

“…Subsequent studies from a variety of laboratories have revealed that a drop in cAMP is a general feature of the initiation of oocyte maturation, including starfish and mouse oocytes (11,12). High cAMP levels in Xenopus oocytes appear to be mediated by elevated adenylyl cyclase, whereas inhibition of phosphodiesterase activity in mouse oocytes keeps cAMP high (13,14).…”

Reversible meiotic arrest in feline oocytes

“…There is a constitutively active adenylate cyclase in mammalian oocytes that produces cAMP (Mehlmann 2005). Recent research in mice has shown that cumulus cells, upon stimulation with natriuretic peptide precursor type C (NPPC), produce cyclic guanosine monophosphate (cGMP), which is transferred into the oocyte via gap junctions and inhibits PDE3 (Norris et al 2009;Zhang et al 2010). The combination of continuous cAMP production and little or no degradation of cAMP by PDE3 results in sufficient concentrations of cAMP within the oocyte to maintain meiotic arrest.…”

“…The combination of continuous cAMP production and little or no degradation of cAMP by PDE3 results in sufficient concentrations of cAMP within the oocyte to maintain meiotic arrest. When the COC is removed from the follicle and the influence of NPPC, cGMP production by the cumulus cells is decreased, PDE activity within the oocyte increases, cAMP concentrations within the oocyte fall and the oocyte resumes meiosis (Norris et al 2009;Zhang et al 2010). Therefore, maintaining meiotic arrest in isolated COCs requires the use of chemicals that can maintain adequate concentrations of cAMP within the oocyte, either by stimulating production via adenylate cyclase or by inhibiting PDE activity, or both.…”