Stochastic fluctuations promote ordered pattern formation of cells in the Notch-Delta signaling pathway

TL;DR

This study demonstrates that intermediate stochastic fluctuations in the Notch-Delta signaling pathway promote the formation of ordered, checkerboard-like cell patterns by facilitating pattern proofreading and reducing disorder, while high noise levels disrupt order.

Contribution

It introduces a stochastic model of the Notch-Delta pathway showing how intermediate noise levels enhance ordered pattern formation in multicellular systems.

Findings

Intermediate fluctuations promote checkerboard pattern formation.

High noise levels disrupt pattern order.

Stochastic noise facilitates pattern proofreading.

Abstract

The Notch-Delta signaling pathway mediates cell differentiation implicated in many regulatory processes including spatiotemporal patterning in tissues by promoting alternate cell fates between neighboring cells. At the multicellular level, this "lateral inhibition" principle leads to checkerboard patterns of Sender and Receiver cells. While it is well known that stochasticity modulates cell fate specification, little is known about how stochastic fluctuations at the cellular level propagate during multicell pattern formation. Here, we model stochastic fluctuations in the Notch-Delta pathway in the presence of two different noise types - shot and white - for a multicell system. The results show that intermediate fluctuations reduce disorder and guide the multicell lattice toward more checkerboard like patterns. By further analyzing cell fate transition events, we demonstrate that intermediate noise amplitudes provide enough perturbation to facilitate "proofreading" of disordered patterns and cause cells to switch to their correct ordered state. Conversely, high noise can override environmental signals coming from neighboring cells and lead to switching between ordered and disordered patterns. Therefore, in analogy with spin glass systems, intermediate noise levels allow the multicell Notch system to escape frustrated patterns and relax towards the lower energy checkerboard pattern while at large noise levels the system is unable to find this ordered base of attraction.