A discrete model of Drosophila eggshell patterning reveals cell-autonomous and juxtacrine effects

The Drosophila eggshell constitutes a remarkable system for the study of epithelial patterning, both experimentally and through computational modeling. Dorsal eggshell appendages arise from specific regions in the anterior follicular epithelium that covers the oocyte: two groups of cells expressing broad (roof cells) bordered by rhomboid expressing cells (floor cells). Despite the large number of genes known to participate in defining these domains and the important modeling efforts put into this developmental system, key patterning events still lack a proper mechanistic understanding and/or genetic basis, and the literature appears to conflict on some crucial points. We tackle these issues with an original, discrete framework that considers single-cell models that are integrated to construct epithelial models. We first build a phenomenological model that reproduces wild type follicular epithelial patterns, confirming EGF and BMP signaling input as sufficient to establish the major features of this patterning system within the anterior domain. Importantly, this simple model predicts an instructive juxtacrine signal linking the roof and floor domains. To explore this prediction, we define a mechanistic model that integrates the combined effects of cellular genetic networks, cell communication and network adjustment through developmental events. Moreover, we focus on the anterior competence region, and postulate that early BMP signaling participates with early EGF signaling in its specification. This model accurately simulates wild type pattern formation and is able to reproduce, with unprecedented level of precision and completeness, various published gain-of-function and loss-of-function experiments, including perturbations of the BMP pathway previously seen as conflicting results. The result is a coherent model built upon rules that may be generalized to other epithelia and developmental systems.
Author Summary We propose a modeling approach to Drosophila egg appendage development. Relying on a thorough compilation of published data, our model comprises cellular genetic networks and cell-cell communication. It proves to be extremely robust by faithfully replicating the wild type pattern as well as patterns arising from mutational perturbations. Our model proposes a new hypothesis for the definition of the anterior competence region, through early posterior EGF activity in conjunction with an early BMP signaling event, which may reconcile apparently conflicting experimental results. Furthermore, this is the first model that explicitly includes the removal of Grk, possibly through vitelline membrane formation, as a central event in patterning the follicular epithelium. Importantly, the model predicts the requirement of an instructive juxtacrine signal to specify the different regions of the developing appendages. Finally, our modeling framework may be applied to other developing epithelia and biological systems.