Cell-Sorting at the A/P Boundary in the DrosophilaWing Primordium: A Computational Model to Consolidate Observed Non-Local Effectsof Hh Signaling

摘要

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. Ourresults suggest a scenario in which homotypic interactions of a putative Hhtarget molecule at the cell surface are converted into a mechanical force. Sucha scenario could explain why the mechanical output of Hh signaling appears to beconfined to the compartment boundary, despite the longer range of the Hhmolecule itself. Our study is the first to couple a cellular vertex modeldescribing mechanical properties of cells in a growing tissue, to an explicitmodel of an entire signaling pathway, including a freely diffusible component.We discuss potential applications and challenges of such an approach.