Robustness of morphogenesis via noise and mechano-chemical feedbacks

Description du projet

Comment la rétroaction mécano-chimique transforme le bruit moléculaire en une morphogenèse robuste

Les tissus vivants se développent en structures remarquablement cohérentes en dépit du comportement apparemment aléatoire et hétérogène des molécules et des cellules qui interagissent pour les former (morphogenèse). Des mécanismes de rétroaction active doivent par conséquent être à la base de cette fiabilité. Le projet REFINE, financé par le CER, entend élucider la rétroaction mécano-chimique qui permet aux tissus embryonnaires de tamponner, et même d’exploiter, cet arrière-plan «bruyant» pour produire des formes robustes et reproductibles. Dans le cadre d’un effort combiné de modélisation et d’expérimentation dans des contextes in vitro et in vivo, REFINE explorera systématiquement la manière dont les forces, les signaux et le bruit agissent ensemble pour maintenir la fiabilité du développement. Les résultats révéleront les principes de conception qui régissent un développement robuste.

Objectif

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.