Signaling networks in somatic cells and oocytes activated during ovulation

Abstract

The molecular and structural changes in the follicle triggered by the gonadotropin luteinizing hormone (LH) at ovulation require complex interactions between somatic cells and the oocytes. It is well established that the signals originating from the oocytes play an essential role in orchestrating the growth and development of the follicle. Conversely, the exact contribution of local signals in the two compartments to ovulation is less clear. LH causes oocyte meiotic resumption, cumulus expansion, and follicle rupture through direct activation of granulosa cells, but also indirectly by acting on cumulus cells and the oocyte. Recent studies from our and other laboratories have identified some of the components of the signaling network activated at this critical transition. The oocyte meiotic arrest is maintained through the activity of GPCR and adenylyl cyclases endogenous to the oocyte and by diffusion of signals through gap junction connections with the soma. It is possible that cAMP, and more recently, cGMP, diffuses through the gap junction network from somatic cells to the oocyte to maintain meiotic arrest. Recent evidence suggests that the biochemical mechanism by which cGMP maintains meiotic arrest is likely through regulation of the oocyte PDE and therefore, indirectly cAMP. The exact series of events regulating reentry of the oocyte into the cell cycle are still not completely understood, but it is widely accepted that a decrease in cAMP is the primary signal. This decrease in cAMP is caused by an activation of the oocyte PDE but also by closure of the gap junctions. The regulatory mechanisms in the soma that lead to activation of the PDE in the oocytes and gap junction closure are the focus of intense investigation. Several signaling pathways converge on these two final events. LH initially activates cAMP signaling but then the stimulus branches into a number of contiguous and interacting pathways. Activation of the EGF network is one of these pathways and accumulating evidence strongly indicates that this is a component critical for oocyte maturation, cumulus expansion, and follicle rupture. Because these regulatory mechanisms are conserved in rodents and in humans, a better understanding of these signaling networks activated during ovulation will provide new pharmacological opportunities for the manipulation of fertility.