Intracellular calcium in the fertilization and development of mammalian eggs

Abstract

1. Mammalian eggs are arrested at metaphase of their second meiotic division when ovulated and remain arrested until fertilized. The sperm delivers into the egg phospholipase C (PLC) zeta, which triggers a series of Ca(2+) spikes lasting several hours. The Ca(2+) spikes provide the necessary and sufficient trigger for all the events of fertilization, including exit from metaphase II arrest and extrusion of cortical granules that block the entry of other sperm. 2. The oscillatory Ca(2+) signal switches on calmodulin-dependent protein kinase II (CaMKII), which phosphorylates the egg-specific protein Emi2, earmarking it for degradation. To remain metaphase II arrested, eggs must maintain high levels of maturation-promoting factor (MPF) activity, a heterodimer of CDK1 and cyclin B1. Emi2 prevents loss of MPF by blocking cyclin B1 degradation, a process that is achieved by inhibiting the activity of the anaphase-promoting complex/cyclosome. However, CaMKII is not the primary initiator in the extrusion of cortical granules. 3. Ca(2+) spiking is also observed in mitosis of one-cell embryos, probably because PLCzeta contains a nuclear localization signal and so is released into the cytoplasm following nuclear envelope breakdown. The function of these mitotic Ca(2+) spikes remains obscure, although they are not absolutely required for passage through mitosis. 4. Intriguingly, the pattern of Ca(2+) spikes observed at fertilization has an effect on both pre- and postimplantation development in a manner that is independent of their ability to activate eggs. This suggests that the Ca(2+) spikes set in train at fertilization are having effects on processes initiated in the newly fertilized egg but whose influences are only observed several cell divisions later. The nature of the signals remains little explored, but their importance is clear and so warrants further investigation.