Enhancer Activity-informed Gap GEne Regulatory Network (EAGER) to model Drosophila gap gene expression on the entire anterior-posterior (A-P) axis

Across metazoa, morphogen gradients differentially regulate gene expression and activate a spatially distinct program to specify body axis development. The Drosophila gap gene network, initiated by maternal morphogen Bicoid, is one of the most well-studied systems. Several regulatory interactions act synergistically to produce distinct gap gene expression patterns along the anterior-posterior (AP) axis of the blastoderm stage Drosophila embryo to ensure the proper segmentation of the larval and, eventually, adult stage fly. Several mathematical models have been proposed to summarize the interconnectivity of gap gene regulatory elements and predict expression in mutant systems. However, these models have not successfully predicted the gap gene expression profile over the entire AP axis. Here, we present an Enhancer Activity-informed Gap GEne Regulatory network (EAGER) model that incorporates enhancer activity-driven differential regulation along the AP axis, which successfully summarizes gap gene expression patterns over the entire AP axis. We validated the predictions of EAGER on Kr mutants and performed a comprehensive parametric sensitivity and identifiability analysis to evaluate the robustness of the EAGER model fits and predictions. We also propose a reduced version of the model, rEAGER, which identifies a minimal set of regulatory interactions and successfully summarizes the gap gene interactions over the entire AP axis. Our results suggest that the expression driven by individual enhancers must be accounted for in models of developmental pattern formation.