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

Cell behaviors 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 signaling range. In many developing epithelia, contact-based Notch-Delta lateral inhibition signaling is used to pattern cell fates. While previous work revealed that cells can use protrusions to extend the range of Notch-Delta signaling 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 neighbors at different heights along their apico-basal axis, effectively increasing the number of neighbors each cell touches. To quantitatively assess this behavior, we develop a mathematical modeling framework (Multilayer Signaling Model) to simulate Notch-Delta signaling over data-derived 3D cell topologies. The model predicts that lateral cell surface signaling is essential to tune the spacing between sensory organ precursors (SOPs). In agreement, we show that perturbing cortical stiffness and cell tortuosity in vivo modifies SOP spacing. These results emphasize the importance of 3D cell geometry and topology in fine-tuning signaling range.