Understanding the Genetic Basis for Biological patterning from the Bottom Up
How genes, operating in individual cells, generate coordinated multicellular behavior is a fundamental question in biology. In every cell, a set of genes interact with one another to control specific cellular functions, and combinations of these functions create population-level behavior, ranging from biological patterns to physiological rhythms. Applying a bottom-up approach, we quantitatively analyzed how tissue patterning dynamics and precision arise from the underlying genetic interactions. Morphogens, forming concentration gradients in space, set the blueprint for tissue patterning. By reconstituting morphogen gradients in vitro, re-wiring genetic interactions, and using quantitative time-lapse imaging and mathematical modeling, we revealed the design principles of a key morphogen pathway, Sonic Hedgehog. Its unique architectural features, including double-negative regulatory logic and an evolutionarily conserved negative feedback loop, together accelerate gradient formation and improve patterning robustness. The ability to isolate morphogen-mediated patterning from concurrent developmental processes and to compare the behavior of alternative pathway architectures offers a new way to uncover developmental design principles and engineer multicellular patterning.