Robustness of morphogenesis via noise and mechano-chemical feedbacks

Projektbeschreibung

Wie mechanochemisches Feedback molekulares Rauschen in robuste Morphogenese verwandelt

Lebende Gewebe entwickeln sich ungeachtet des scheinbar zufälligen und heterogenen Verhaltens der Moleküle und Zellen, die bei ihrer Entstehung miteinander interagieren, zu bemerkenswert konsistenten Strukturen (Morphogenese). Dieser Zuverlässigkeit müssen demzufolge aktive Rückkopplungsmechanismen zugrunde liegen. Das Ziel des ERC-finanzierten Projekts REFINE lautet, das mechanochemische Feedback zu entschlüsseln, das es embryonalen Geweben ermöglicht, diesen „verrauschten“ Hintergrund zu puffern – und sogar zu nutzen –, um robuste, reproduzierbare Formen zu erzeugen. Anhand einer Kombination aus Modellierung und Experimenten, die sowohl in vitro als auch in vivo durchgeführt werden, wird das Team von REFINE systematisch untersuchen, wie Kräfte, Signale und Rauschen zusammenwirken, um Zuverlässigkeit in der Entwicklung beizubehalten. Die Ergebnisse werden die eine robuste Entwicklung lenkenden Gestaltungsprinzipien erkennen lassen.

Ziel

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.