Dr Jonathan Harrison: Testing models of mRNA localization reveals robustness regulated by reducing transport between cells

Robust control of gene expression in both space and time is of central importance in the regulation of cellular processes, and for multicellular development. However, the mechanisms by which robustness is achieved are generally not identified or well understood. Here we use a combined experimental-theoretical approach to characterize the robustness of gurken/TGF-alpha mRNA localization in Drosophila egg chambers, where the oocyte and 15 surrounding nurse cells are connected in a stereotypic network via intracellular bridges known as ring canals. We construct a mathematical model that encodes simplified descriptions of the range of steps involved in mRNA localization, including production and transport between and within cells until the final destination in the oocyte. Using Bayesian inference, we calibrate this model using quantitative single molecule fluorescence in situ hybridization data. By analyzing both the steady state and dynamic behaviours of the model, we provide estimates for the rates of different steps of the localization process, as well as the extent of directional bias in transport through the ring canals. The model predicts that mRNA synthesis and transport must be tightly balanced to maintain robustness, a prediction which we tested experimentally using an over-expression mutant. Surprisingly, the over-expression mutant fails to display the anticipated degree of overaccumulation of mRNA in the oocyte predicted by the model. Through careful model-based analysis of quantitative data from the over-expression mutant we show evidence of saturation of transport of mRNA through ring canals. We conclude that this saturation engenders robustness of the localization process, in the face of significant variation in the levels of mRNA synthesis