Synthetic Notch Activation Patterns in a Proliferating Tissue

Cell-cell communication through direct contact is essential during fundamental biological processes such as tissue repair and morphogenesis. Synthetic forms of contact-mediated cell-cell communication can generate custom gene expression outputs, making them valuable for tissue engineering and regenerative medicine. To precisely control the location and timing of synthetic signal outputs in growing tissues, it is necessary to understand the mechanisms underlying its spatiotemporal patterns. Towards this goal, we combine theory and experiments to study patterns of synthetic Notch (synNotch) activation - a custom synthetic gene circuit that we implement within Drosophila wing imaginal discs. We show that output synthesis and degradation rates together with cell division are the key minimal parameters that predict the heterogeneous spatiotemporal patterns of synNotch activation. Notably, synNotch output forms a graded exponential spatial profile that extends several cell diameters from the signal source, establishing evidence for signal propagation without diffusion or long range cell-cell communication. Furthermore, we discover that the shape of the interface between ligand and receptor cells is important in determining the synNotch output. Overall, we elucidate key biophysical principles that underlie complex emergent spatiotemporal patterns of synNotch output in a growing tissue.