We are using gene circuit models to study pattern formation in early embryogenesis of the fruit fly Drosophila melanogaster. The central goal of the project is to show how regulatory interactions among segmentation genes can lead to observed patterns of gene expression, and hence to determination of the segmented body plan of Drosophila.
The gene circuit approach is a data-driven mathematical modeling method to study regulatory gene networks. It is used to infer regulatory interactions among segmentation genes based on quantified wild type gene expression data from the FlyEx database (see also Quantitative Data Acquisition). This is achieved by fitting gene circuit models to data by a least squares fitting method using Parallel Lam Simulated Annealing (PLSA). Regulatory interactions are defined by regulatory parameters in the model equations. PLSA provides an algorithm for altering and selecting these model parameters in a way which allows us obtain gene circuit models that reproduce the observed gene expression patterns as closely as possible.
Parameters of gene circuit models contain information about regulatory mechanisms underlying the gene expression patterns used for optimization. This information can be extracted from the models by graphical analysis of regulatory contributions to gene expression in gene circuits.
The gene circuit approach has been successfully applied to analysis of gap and pair-rule gene expression. It was used to predict regulatory synergy between maternal Bcd and Hb. Regulatory analysis of the pair-rule gene even-skipped (eve) revealed that correct timing of eve stripe formation depends on refinement and intensification of gap domains. Correct formation of eve stripes also depends on limited diffusivity of the Eve protein due to apical localization and entrapment of the protein by invaginating cell membranes during cleavage cycle 14A. Lastly, we showed that the eve expression pattern is the only pair-rule expression pattern which can arise from gap gene regulatory inputs only.
Most recently, gap gene circuits have been used to investigate the role of nuclear divisions in Drosophila segment determination and to analyze dynamical regulatory mechanisms underlying gap gene expression. This analysis resulted in clarification of several ambiguities in the experimental literature and yielded a prediction of a novel regulatory interaction between Cad and Kr. Moreover, it was successfully applied to study the regulatory mechanism for shifts in gap gene domains (for further information go here).