Multiple Notch ligands in the synchronization of the segmentation clock

TL;DR

This paper develops a theoretical model to understand how multiple Delta ligands with different properties influence Notch signaling during embryonic segmentation, revealing their distinct roles in collective oscillations.

Contribution

It introduces a novel theory describing interactions between biochemical oscillators with multiple Delta ligands, and compares two hypotheses for ligand binding mechanisms in Notch signaling.

Findings

Both hypotheses can explain experimental data.

Different roles assigned to non-oscillatory ligands in each model.

Proposes experiments to distinguish ligand binding mechanisms.

Abstract

Notch signaling is a ubiquitous and versatile intercellular signaling system that drives collective behaviors and pattern formation in biological tissues. During embryonic development, Notch is involved in generation of collective biochemical oscillations that form the vertebrate body segments, and its failure results in embryonic defects. Notch ligands of the Delta family are key components of this collective rhythm, but it is unclear how different Delta ligands with distinct properties contribute to relaying information among cells. Motivated by the zebrafish segmentation clock, in this work we propose a theory describing interactions between biochemical oscillators, where Notch receptor is bound by both oscillatory and nonoscillatory Delta ligands. Based on previous in vitro binding studies, we first consider Notch activation by Delta dimers. This hypothesis is consistent with experimental observations in conditions of perturbed Notch signaling. Then we test an alternative hypothesis where Delta monomers directly bind and activate Notch, and show that this second model can also describe the experimental observations. We show that these two hypotheses assign different roles for a non-oscillatory ligand, as a binding partner or as a baseline signal. Finally, we discuss experiments to distinguish between the two scenarios. Broadly, this work highlights how a multiplicity of ligands may be harnessed by a signaling system to generate versatile responses.