PLoS Computational Biology, 2011, Vol.7(4), p.e1002025
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. ; In developing animal tissues, cells can often re-arrange locally and mix relatively freely. However, in some stereotypic and crucially important instances during body development, cells will strictly not intermingle, and instead form sharp boundaries along which they will sort out from each other. This mechanism helps organisms to establish signaling centers and to maintain distinct cellular identities. Often, cells at such boundaries will remain in close physical contact and are morphologically alike. Thus, the boundary itself can be difficult to observe unless the expression status of specific marker genes is monitored experimentally. How are these ‘compartment boundaries’ established? Here we devise a computational model that aims to describe one such boundary in a well-studied animal tissue: the developing wing primordium of . We model the production, diffusion and local sensing of an essential signaling molecule, the protein. We reveal one possible mechanism by which Hedgehog sensing can influence the mechanical properties of cells, and compare the simulated outcome to observations in experimentally perturbed, actual wing discs. Our relatively simple model suffices to establish a straight and stable compartment boundary.
Research Article ; Biology ; Computational Biology ; Developmental Biology