Emergent spatiotemporal patterning of synthetic Notch signal transduction in vivo .

Cell-cell communication through direct contact is essential during multiple fundamental biological processes. Synthetic forms of contacted-mediated cell-cell communication can generate custom gene expression outputs, making them valuable for tissue engineering and regenerative medicine. Mechanisms underlying the spatiotemporal behavior of synthetic signal outputs in growing tissues, necessary to precisely control the output location and timing, are not well understood. Towards this goal, we combine theory and quantitative experiments to study patterns of synthetic Notch (synNotch) activation a custom synthetic gene circuit that we implement within growing Drosophila wing imaginal discs. We show that cell growth, division, output synthesis and degradation are the key minimal parameters that predict the heterogenous spatiotemporal patterns of synNotch activation in tissues. At long times, synNotch output forms a graded exponential spatial profile that extends several cell diameters from the signal source, indicating a role of cell division in signal propagation. 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 growing tissues.