Robustness of morphogenesis via noise and mechano-chemical feedbacks

Objective

Development involves increasingly intricate processes of physical tissue sculpting (morphogenesis), resulting in highly reproducible shapes. The apparent paradox between reproducibility at macroscopic scales, and emerging evidence of extensive heterogeneity and stochasticity at the molecular and cellular scales, suggests that active mechanisms are necessary to ensure morphogenetic robustness. However, as biomechanical theories of morphogenesis have largely ignored the presence and many facets of noise, robustness remains poorly defined. We hypothesize that mechano-chemical feedbacks between signaling, forces and geometry provide correction mechanisms that not only mitigate noise, but can also, counterintuitively, leverage it to drive robust morphogenesis. By deriving generic noisy mechano-chemical models, we will systematically quantify and dissect the efficiency of different feedback mechanisms underlying morphogenetic robustness, for different physiologically-relevant noise sources. Predictions will be tested via experimental collaborations in selected in vitro and in vivo contexts, where feedbacks and noise can be tuned. We will follow three independent, yet complementary, aims: Aim 1: Understand how forces, signaling, and noise interact to achieve robust temporal coordination and spatial symmetry during morphogenesis. Aim 2: Define whether and how noisy initial and boundary conditions act as a source of robust morphogenetic information. Aim 3: Develop frameworks for unbiased inference of noise and robustness mechanisms from complex morphogenetic datasets. Recent advances in high-throughput experiments, computational analyses and biophysical theories make it an ideal time to address this longstanding question. With a strong foundation in data-driven modeling of biological stochasticity, cell mechanics and tissue self-organization, our lab is uniquely poised to provide fundamental insights into the design principles underpinning robust development.