Link between fertilization-induced Ca2+ oscillations and relief from metaphase II arrest in mammalian eggs: a model based on calmodulin-dependent kinase II activation

Abstract

Mammalian eggs are ovulated in metaphase II of meiosis, in a state characterized by high levels of cyclin B and of active maturation promoting factor (MPF). This arrest is mediated by an activity referred to as cytostatic factor (CSF) which prevents the degradation of cyclin. Fertilization triggers a train of Ca2+ spikes which is responsible for the decrease in activity of both MPF and CSF. The decline in MPF however much precedes that in CSF. Experimental observations on mammalian eggs indicate that the kinetics of cell cycle resumption much depends on the temporal pattern of the repetitive Ca2+ spikes. Here, we propose a theoretical model which accounts for Ca(2+)-induced relief from metaphase II arrest in mammalian eggs. The model is based on the fact that Ca2+/calmodulin kinase II (CaMKII) activation is the primary event leading to inactivation of both CSF and MPF. To account for experimental observations, it has to be assumed that CaMKII activation affects the level of the active form of the anaphase promoting complex (APC), which initiates the degradation of cyclin, through two pathways characterized by different time scales. Thus, we hypothesize that CaMKII activation by Ca2+ leads to the transformation of a mediator protein from a form which stimulates the inactivation of the APC into a form which gradually and indirectly induces the deactivation of CSF. In consequence, a sufficient number of Ca2+ spikes first triggers the decrease of MPF, thus allowing the egg to enter in interphase, and later that of CSF. Finally, when CSF is low and when Ca2+ oscillations have stopped, the level of MPF can increase again, a phenomenon that would correspond to the first mitosis. This model also accounts for the observed dependence of the time of entry in interphase (marked by the appearance of the pronuclei) on the frequency of Ca2+ spikes, as well as for the possible entry in metaphase III arrest, a pathological state of the egg which results from an insufficient activation by Ca2+. This study provides some theoretical prediction as to the time of the first mitosis as a function of the temporal pattern of Ca2+ oscillations.