Int. J. Dev. Biol. 54: 655 - 665 (2010)

https://doi.org/10.1387/ijdb.082845gd

Vol 54, Issue 4

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

Original Article | Published: 8 January 2010

Geneviève Dupont*^,1, Elke Heytens² and Luc Leybaert³

¹Unité de Chronobiologie Théorique, Université Libre de Bruxelles, Brussels, ² Department of Reproductive Medicine, Ghent University Hospital, Ghent and ³Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium

Abstract

Fertilization in mammals is accompanied by Ca²⁺ oscillations in the egg cytoplasm, leading to exit from meiosis and entry into the first embryonic cell cycle. The signal transduction pathway linking these Ca²⁺ 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 Ca²⁺ increases. Using a model for CaMKII activation that reproduces the frequency sensitivity of this kinase, simulations confirm that Ca²⁺ spikes are accompanied by in phase variations in the level of CaMKII activity and suggest that in most mammalian species, Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ ionophores.

Keywords

CaMKII, in vitro fertilization, calcium ionophore, assisted oocyte activation (AOA)