Coordination of Morphogenetic Growth and Cellular Mechanics across Multiple Cell Layers to Shape the Drosophila Wing Disc

Abstract

Epithelia serve as barriers between the environment and internal structures of organs. Epithelial morphogenesis must be carefully controlled through coordination of cellular properties. This is critical because uncontrolled epithelial growth is the underlying cause of more than ninety percent of tumors. However, how mechanical properties are patterned across multiple cell layers to define overall organ shape during development is poorly understood. Additionally, how cells regulate their heights and remodel the extracellular matrix during organ growth is still largely unknown. Here, we define the contributions of multiple epithelial cell types (squamous, cuboidal and columnar) to the shaping of the Drosophila wing imaginal disc. The wing disc has long served as a paradigm model system to study epithelial morphogenesis due to the ability to selectively manipulate cell mechanics within the tissue. The wing disc becomes progressively more folded and buckled as the organ grows to its final size. Coupled computational simulations and experiments demonstrate that overall organ shape depends on several factors: differential regulation of growth rates between cell types, spatial patterning of mechanical properties across the tissue, and regulation of the underlying extracellular matrix surrounding the organ. The computational model couples a novel subcellular element (SCE) model representing cell mechanics and a discrete sub-model describing how chemical signaling patterns the subcellular mechanical properties of cells. Computational predictions are validated through both pharmacological and genetic perturbations of known regulators of epithelial morphogenesis, including the bone morphogenetic protein Decapentaplegic (DPP) and regulators of actomyosin contractility. This work describe a powerful computational platform for evaluating mechanisms of three-dimensional epithelial morphogenesis through feedback between multi-scale computational modeling and experimentation.