Publications

Mammalian oocytes are arrested at prophase of the first meiotic division before induction of maturation by the preovulatory LH surge. In vitro, oocyte maturation occurs spontaneously. The first meiotic arrest is characterized by a large nucleus called the germinal vesicle. One important signaling molecule for resumption of meiosis is cyclic AMP (cAMP). High levels of cAMP block spontaneous meiotic resumption. Research investigating the regulation of oocyte cAMP has led to the discovery of new receptors, guanosine 5'-triphosphate-binding (G) proteins, cyclases, and phosphodiesterases. Leydig insulin-like 3, a polypeptide growth factor of the insulin family, is expressed in thecal cells. Leydig insulin-like 3 activates the Leu-rich, repeat-containing, G protein-coupled receptor 8, which is expressed in the oocyte. Coupled to the inhibitory GTP binding protein, this receptor leads to a decrease in cAMP production. Treatment with Leydig insulin-like 3 polypeptide initiates meiotic progression of oocytes in preovulatory follicles, demonstrating the importance of cAMP management for meiotic resumption. Furthermore, microinjection of an antibody against stimulatory G protein (Gs) into mouse oocytes results in meiotic resumption, suggesting that meiotic arrest of the oocyte is dependent on Gs activity. The orphan Gs-linked receptor, GPR3, is expressed in the oocyte. The oocytes of GPR3-null mice resume meiosis when still in their follicles, suggesting that GPR3 is involved in the control of cAMP production and thus meiotic arrest. Cyclic nucleotides are synthesized by cyclases and degraded by phosphodiesterases. Mouse and rat oocytes express isoform 3 of adenylyl cyclase. In the mouse, the null mutation results in approximately 50% of the oocytes resuming meiosis, demonstrating the importance of the synthesis of cAMP in controlling nuclear maturation. The null mutation of the major phosphodiesterase expressed in mouse oocytes results in female sterility due to ovulation of meiotically arrested oocytes that cannot be fertilized. Maintenance of meiotic arrest is explained by constitutive cAMP signaling associated with undetectable cAMP-phosphodiesterase activity. Collectively, these results are beginning to illuminate the key signaling molecules involved in the control of intraoocyte cAMP levels, thus regulating the arrest and resumption of meiosis.