Stochastic Noise and Synchronisation during Dictyostelium Aggregation Make cAMP Oscillations Robust

Stable and robust oscillations in the concentration of adenosine 3′, 5′-cyclic monophosphate (cAMP) are observed during the aggregation phase of starvation-induced development in Dictyostelium discoideum. In this paper we use mathematical modelling together with ideas from robust control theory to identify two factors which appear to make crucial contributions to ensuring the robustness of these oscillations. Firstly, we show that stochastic fluctuations in the molecular interactions play an important role in preserving stable oscillations in the face of variations in the kinetics of the intracellular network. Secondly, we show that synchronisation of the aggregating cells through the diffusion of extracellular cAMP is a key factor in ensuring robustness of the oscillatory waves of cAMP observed in Dictyostelium cell cultures to cell-to-cell variations. A striking and quite general implication of the results is that the robustness analysis of models of oscillating biomolecular networks (circadian clocks, Ca2+ oscillations, etc.) can only be done reliably by using stochastic simulations, even in the case where molecular concentrations are very high.: The molecular network, which underlies the oscillations in the concentration of adenosine 3′, 5′-cyclic monophosphate (cAMP) during the aggregation phase of starvation-induced development in Dictyostelium discoideum, achieves remarkable levels of robust performance in the face of environmental variations and cellular heterogeneity. However, the reasons for this robustness remain poorly understood. Tools and concepts from the field of control engineering provide powerful methods for uncovering the mechanisms underlying the robustness of these types of biological systems. Using such methods, two important factors contributing to the robustness of cAMP oscillations in Dictyostelium are revealed. First, stochastic fluctuations in the molecular interactions of the intracellular network, arising from random or directional noise and biological sources, play an important role in preserving stable oscillations in the face of variations in the kinetics of the network. Second, synchronisation of the aggregating cells through the diffusion of extracellular cAMP appears to be a key factor in ensuring robustness to cell-to-cell variations of the oscillatory waves of cAMP observed in Dictyostelium cell cultures. The conclusions have important general implications for the robustness of oscillating biomolecular networks (whether seen at organism, cell, or intracellular levels and including circadian clocks or Ca2+ oscillations, etc.), and suggest that such analysis can be conducted more reliably by using models including stochastic simulations, even in the case where molecular concentrations are very high.