Synchronization of the segmentation clock using synthetic cell–cell signaling

During vertebrate development, the segmentation clock drives oscillatory gene expression in the presomitic mesoderm (PSM), leading to the periodic formation of somites. Oscillatory gene expression is synchronized at the cell population level; inhibition of Delta–Notch signaling results in the loss of synchrony and the fusion of somites. However, it remains unclear how cell–cell signaling couples oscillatory gene expression and controls synchronization. Here, we report that synthetic cell–cell signaling using designed ligand–receptor pairs can induce synchronized oscillations in PSM organoids. Optogenetic assays uncovered that the intracellular domains of synthetic ligands play key roles in dynamic cell–cell communication. Oscillatory coupling using synthetic cell–cell signaling recovered the synchronized oscillation in PSM cells deficient for Delta–Notch signaling; nonoscillatory coupling did not induce recovery. This study reveals the mechanism by which ligand–receptor molecules coordinate the synchronization of the segmentation clock and provides a way to program temporal gene expression in organoids and artificial tissues.