ROLE OF PHOSPHODIESTERASES IN GAMETOGENESIS

Stanford University, Stanford CA

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Abstract

After a prolonged meiotic arrest that may last for years, oocyte resume meiosis a few hours before ovulation. It is established that the pre- ovulatory gonadotropin surge is the physiological trigger for meiotic resumption, but little is known about the signals that are exchanged between granulosa cells and oocytes that are required for completion of meiosis in mammals. Similarly, little is known about the initial signaling events that, in the oocyte, occur prior to reentry into the cell cycle, even though it is widely accepted that cyclic nucleotides play a critical role in the control of this process. The correct execution of the maturation meiotic division is essential for fertility, because oocytes that are arrested in meiotic prophase cannot be fertilized. Using several independent approaches, we have determined that cAMP hydrolysis in oocytes and granulosa cells is mediated by different phosphodiesterases (PDEs) and that this compartmentalization can be exploited to manipulate the cyclic AMP pools in somatic or germ cell compartments independently. The PDE expressed in the oocytes was cloned and characterized and inhibitors specific for this isoform block meiotic resumption in vitro and in vivo. In addition, we have identified tow kinase upstream of this PDE using a reconstitution strategy in Xenopus oocytes. To further determine the role of cAMP signaling in the maintenance of meiotic arrest and in meiotic resumption, we have established mouse models where the cAMP pathway is disrupted via inactivation of the PDEs expressed in oocytes and granulosa cells, respectively. We propose to use these genetically altered mice to understand how cAMP is regulated prior to meiotic resumption in the somatic and germ cell compartments, how PDE3A is regulated, and its role in resumption of meiosis. Finally, the analysis of the phenotype of the PDE null mice will allow us to determine the role of cAMP in signaling between granulosa cells and oocytes and its role in ovulation. Because we have demonstrated that interference with meiotic resumption is a viable strategy for fertility control, the information obtained is of great potential for the development of new contraceptive agents that are devoid of the undesirable side effects of conventional hormonal contraceptives.