3D epithelial cell topology tunes signalling range to promote precise patterning

Abstract

Cell behaviours in multicellular organisms are coordinated via both diffusible molecules and by signals based on direct cell-cell contacts. The mode of cell communication used influences the signalling range. In many developing epithelia, contact-based Notch-Delta lateral inhibition signalling is used to pattern cell fates. While previous work revealed that cells can use protrusions to extend the range of Notch-Delta signalling to alter these patterns, this is not a general feature of epithelia. In addition, it is not known how the complex three-dimensional (3D) shapes of epithelial cells influence cell communication. In exploring this question, we show that epithelial cells at the Drosophila wing margin, which lack basal protrusions, contact different neighbours at different heights along their apico-basal axis, effectively increasing the number of neighbours each cell touches. To quantitatively assess this behaviour, we develop a novel mathematical modelling framework (Multi-layer Signalling Model) to simulate Notch-Delta signalling over data-derived 3D cell topologies. The model predicts that lateral cell surface signalling is essential to tune the spacing between SOPs. In agreement, we show that perturbing cortical stiffness and cell tortuosity in vivo modifies SOP spacing. These results emphasise the importance of 3D cell geometry and topology in fine-tuning signalling range.