A Discrete Model of Drosophila Eggshell Patterning Reveals Cell-Autonomous and Juxtacrine Effects

Abstract

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.

Gene regulation during Drosophila eggshell patterning

“…The experimental studies of this system have come a long way from the identification of the key components of signaling pathways through their effects on eggshell morphologies to the detailed analysis of gene regulatory sequences and computational models that capture multiple aspects of signaling, transcription, and morphogenesis (30,46,47). Much work remains to be done to characterize the regulatory sequences and their control by transcription factors.…”

EpiLog: A software for the logical modelling of epithelial dynamics

“…EpiLog window is shown in Figure 2A, with the simulation panel displaying the stable pattern obtained with this model. The remaining panels C–G show different states of the grid, with panels F–G recapitulating patterns resulting from model perturbations (see Figures 6–8 in 5). …”

“…The logical model defined by Fauré et al reproduces the patterning of the anterior follicular epithelium of the oocyte, defining the floor (Rho expressing cells) and roof (Br expressing cells) of the future appendages 5 . The model is provided in Supplementary Model File 2.…”

“…( C ) Grk and Dpp gradient defined as positional inputs in EpiLog. ( D ) Stable pattern obtained with a simulation starting from the pattern displayed in panel A and without the Grk signal (phase 2), suggesting that Grk extinction is required to split the floor regions (see 5). ( E ) EpiLog simulation of a mild overexpression of Dpp.…”

“…The consideration of ensembles of communicating cells is often required to recapitulate observed patterns (e.g. 4, 5). …”