It is well established that cAMP signaling is an important regulator of the oocyte meiotic cell cycle. Conversely, the function of cGMP during oocyte maturation is less clear. Herein, we evaluated the expression of cGMP-hydrolyzing phosphodiesterases (PDEs) in the somatic and germ cell compartments of the mouse ovarian follicle and demonstrate that PDE5 is preferentially expressed in somatic cells. Cyclic GMP is a potent inhibitor of cAMP hydrolysis from oocyte extracts, with a 50% inhibitory concentration of 97 nM. Luteinizing hormone (LH) stimulation of cultured preovulatory follicles results in a marked decrease in cGMP content, and a nadir is reached in 1.5 h; similarly, oocyte cGMP levels decrease after gonadotropin stimulation in vivo. The LH-dependent decrease in cGMP requires activation of the epidermal growth factor network. Treatment of follicles with a PDE5 inhibitor increases cGMP in the follicle well above unstimulated levels. Although LH causes a decrease in cGMP in follicles preincubated with PDE5 inhibitors, the levels of this nucleotide remain above unstimulated levels. Under these conditions of elevated cGMP, LH stimulation does not cause oocyte maturation after 5 h of incubation. Microinjection of a cGMP-specific PDE into oocytes causes meiotic maturation of wild-type oocytes, suggesting that an intraoocyte pool of cGMP is involved in the maintenance of meiotic arrest. This effect is absent in PDE3A-deficient oocytes. Taken together, these findings provide evidence that cGMP and cAMP signaling cooperate in maintaining meiotic arrest via regulation of PDE3A and that a decrease in cGMP in the somatic compartment is one of the signals contributing to meiotic maturation.

In the preovulatory ovarian follicle, mammalian oocytes are maintained in prophase meiotic arrest until the luteinizing hormone (LH) surge induces reentry into the first meiotic division. Dramatic changes in the somatic cells surrounding the oocytes and in the follicular wall are also induced by LH and are necessary for ovulation. Here, we provide genetic evidence that LH-dependent transactivation of the epidermal growth factor receptor (EGFR) is indispensable for oocyte reentry into the meiotic cell cycle, for the synthesis of the extracellular matrix surrounding the oocyte that causes cumulus expansion, and for follicle rupture in vivo. Mice deficient in either amphiregulin or epiregulin, two EGFR ligands, display delayed or reduced oocyte maturation and cumulus expansion. In compound-mutant mice in which loss of one EGFR ligand is associated with decreased signaling from a hypomorphic allele of the EGFR, LH no longer signals oocyte meiotic resumption. Moreover, induction of genes involved in cumulus expansion and follicle rupture is compromised in these mice, resulting in impaired ovulation. Thus, these studies demonstrate that LH induction of epidermal growth factor-like growth factors and EGFR transactivation are essential for the regulation of a critical physiological process such as ovulation and provide new strategies for manipulation of fertility.The luteinizing hormone (LH) surge plays a central role in promoting a cascade of events in ovarian preovulatory follicles that are essential for the ovulation of a fertilizable oocyte. Acting through LH-chorionic gonadotropin (LH-CG) receptors (LHRs) (LHR is a member of the G protein-coupled receptor superfamily encoded by Lhcgr), LH induces reprogramming of the gene expression profiles of follicular somatic cells (theca and granulosa cells), changes in the secretory properties of the cumulus cells surrounding the oocyte and cumulus expansion, oocyte reentry into the meiotic cell cycle, and follicle rupture (7, 41). LHRs are highly expressed on the granulosa cells lining the antral cavity of preovulatory follicles (mural granulosa cells) and on the external theca cells that are in continuity with the surrounding stroma. However, within preovulatory follicles, oocytes and cumulus cells that are profoundly affected by the LH surge express few or no LHRs and fail to respond when directly exposed to LH in vitro (37).To explain how LH signals are propagated from the periphery toward the cumulus oocyte complex (COC), a model has been proposed whereby factors released by mural granulosa cells function in an autocrine and paracrine manner to transduce the LH effects within the follicle (34). Secretion of bioactive growth factors from the oocyte to affect somatic cells is well established (27,30); conversely, the paracrine signals originating from the somatic cells and affecting oocytes have long been sought but are largely unknown. Recently, we have proposed that intrafollicular release of members of the epidermal growth factor (EGF)-like family (34) may fulfill this ...

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