Oscillatory Ca2+ dynamics and cell cycle resumption at fertilization in mammals: a modelling approach

Abstract

Fertilization in mammals is accompanied by Ca(2+) oscillations in the egg cytoplasm, leading to exit from meiosis and entry into the first embryonic cell cycle. The signal transduction pathway linking these Ca(2+) changes to cell-cycle related kinases has not yet been fully elucidated, but involves activation of calmodulin-dependent kinase II (CaMKII). Here, we develop a computational model to investigate the mechanism by which cell cycle resumption can be sensitive to the temporal pattern of Ca(2+) increases. Using a model for CaMKII activation that reproduces the frequency sensitivity of this kinase, simulations confirm that Ca(2+) spikes are accompanied by in phase variations in the level of CaMKII activity and suggest that in most mammalian species, Ca(2+) spikes are well suited to maximize CaMKII activation. The full model assumes that CaMKII brings about a decrease in the level of cyclinB-cdk1 by two pathways, only one of which is CSF-dependent. Parameters are selected to account for the experimental observations where mouse eggs were artificially activated by different Ca(2+) stimulatory protocols. The model is then used in the context of 'assisted oocyte activation (AOA)' to investigate why the best rates of successful activation are obtained when eggs are submitted to two applications of Ca(2+) ionophores.