# Rewiring gene circuits to dissect oscillatory signaling dynamics

## TL;DR

This paper explores how synthetic biology and optogenetics can be used to study and control oscillatory signaling in developing embryos.

## Contribution

The study introduces a synthetic DELTA–NOTCH pathway and optogenetic tools to investigate intercellular communication in the segmentation clock.

## Key findings

- A synthetic DELTA–NOTCH pathway restored cell–cell communication in DELTA-deficient organoids.
- Optogenetic activation showed that ligand presentation dynamics are crucial for effective signaling.
- The work provides a blueprint for using synthetic circuits to study developmental signaling.

## Abstract

In this Outlook, van Oostrom and Sonnen discuss a study in this issue of Genes & Development that uses an optogenetic approach to study oscillatory intercellular communication through synthetic ligand–receptor pairs during segmentation clock synchronization. They highlight the value of such tools in studying or even reprogramming developmental signaling and gene expression dynamics, which would have implications for regenerative medicine and synthetic embryology.

Precise intercellular communication is critical for cellular decision-making. The segmentation clock is an oscillatory gene network regulating periodic segmentation of the presomitic mesoderm (PSM) in vertebrate embryos. Oscillations between neighboring cells are thought to be coupled by DELTA–NOTCH signaling. To directly test this experimentally, Isomura and colleagues (doi:10.1101/gad.352538.124) reconstituted this coupling using synthetic biology. They integrated a synthetic DELTA–NOTCH pathway into DELTA-deficient PSM organoids, which restored cell–cell communication. Additionally, optogenetic activation of the synthetic ligand further revealed that the dynamics of ligand presentation are crucial for effective communication. This work directly demonstrates the importance of oscillatory cell–cell signaling in development and provides a blueprint for using synthetic circuits in future studies.