Dynamics of emergent spatiotemporal patterning of synthetic Notch signal transduction in vivo.

Juxtacrine signaling is a cell communication process mediated by a ligand on a cell surface binding to a specific receptor on a neighboring cell. Customizable cellular signaling systems, such as synthetic notch signaling system (synNotch) can be used to precisely control the location and timing of synthetic signal outputs in proliferating tissues. SynNotch, based on the native Notch signaling pathway, transduces a unique input signal in the receiving cell due to contact with a neighboring ligand cell to produce a custom gene expression output. In close experimental collaboration, the synNotch output patterns, visualized with the green fluorescent protein (GFP), are quantified in the developing fruit fly larvae. 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. We present a vertex-based computational model to study synNotch signaling in proliferating tissue and 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. Furthermore, we discover that the shape of the interface between ligand and receptor cells is important in determining the synNotch output. We extract cell size and shape parameters and the intensity of the GFP response to evaluate and quantify biophysical trends underlying synthetic cell-cell signaling. As cells undergo dramatic changes in size and morphology during development, our results show that cell size could affect cellular communication.