Cell-Sorting at the A/P Boundary in the Drosophila Wing Primordium: A Computational Model to Consolidate Observed Non-Local Effects of Hh Signaling

Abstract

Non-intermingling, adjacent populations of cells define compartment boundaries; such boundaries are often essential for the positioning and the maintenance of tissue-organizers during growth. In the developing wing primordium of Drosophila melanogaster, signaling by the secreted protein Hedgehog (Hh) is required for compartment boundary maintenance. However, the precise mechanism of Hh input remains poorly understood. Here, we combine experimental observations of perturbed Hh signaling with computer simulations of cellular behavior, and connect physical properties of cells to their Hh signaling status. We find that experimental disruption of Hh signaling has observable effects on cell sorting surprisingly far from the compartment boundary, which is in contrast to a previous model that confines Hh influence to the compartment boundary itself. We have recapitulated our experimental observations by simulations of Hh diffusion and transduction coupled to mechanical tension along cell-to-cell contact surfaces. Intriguingly, the best results were obtained under the assumption that Hh signaling cannot alter the overall tension force of the cell, but will merely re-distribute it locally inside the cell, relative to the signaling status of neighboring cells. Our results suggest a scenario in which homotypic interactions of a putative Hh target molecule at the cell surface are converted into a mechanical force. Such a scenario could explain why the mechanical output of Hh signaling appears to be confined to the compartment boundary, despite the longer range of the Hh molecule itself. Our study is the first to couple a cellular vertex model describing mechanical properties of cells in a growing tissue, to an explicit model of an entire signaling pathway, including a freely diffusible component. We discuss potential applications and challenges of such an approach.

Vertex models: from cell mechanics to tissue morphogenesis

“…The image shows the final shape of a growing epithelium with a morphogen concentration indicated in shades of green (from [23]). ( bottom left ) Interface smoothing between differently fated epithelia due to differential tension [25,30,67]. The image shows a simulation of the boundary between two compartments (red and blue) of the wing imaginal disc in Drosophila (from [25]).…”

A local difference in Hedgehog signal transduction increases mechanical cell bond tension and biases cell intercalations along the Drosophila anteroposterior compartment boundary

“…The signals that result in the local increase in cell bond tension along compartment boundaries, however, are not known. It has been proposed that local increases in cell bond tension result from Hedgehog signaling across the AP boundary (Landsberg et al, 2009;Schilling et al, 2011).…”

A node-based version of the cellular Potts model

“…In particular, these authors assume that the rate of cell growth linearly increases with the local concentration of the given chemical substance. Schilling and coworkers instead employ and modify the energy-based model by Farhadifar in the context of the cell sorting at the anterior/posterior boundary in the Drosophila wing primordium [89]. They assume that the bond tensions Λ ij in Eq.…”