Rewiring gene circuits to dissect oscillatory signaling dynamics

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.