Understanding signaling dynamics through synthesis.

Tissue-scale organization emerges from the action of sophisticated multiscale developmental programs. But the design rules for composing elementary signaling and information processing modules into such functional systems and for integrating them into the noisy and convoluted living context remain incompletely addressed. The construction of a synthetic gene circuit encoding contact-dependent signal propagation demonstrates one broadly applicable approach to this problem. The circuit comprises orthogonal signaling through the Delta ligand and the Notch receptor, multicellular positive feedback, and transcriptional signal amplification. Positive feedback and contact signaling proved sufficient for bistability and signal propagation across a population of mammalian cells, but only when combined with signal amplification. Thus, construction and characterization of synthetic gene circuits have made it possible to establish mechanistic sufficiency and the minimal requirements for the phenotype of interest.