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Synchronization of the segmentation clock using synthetic cell-cell signaling.

Akihiro Isomura1,2,3,4, Daisuke Asanuma3,5, Ryoichiro Kageyama6,4

  • 1Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; aisomura@infront.kyoto-u.ac.jp ryoichiro.kageyama@riken.jp.

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|October 16, 2025
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Synthetic cell signaling synchronizes the segmentation clock in vertebrate development. This research clarifies how ligand-receptor interactions coordinate gene oscillations, enabling programmed temporal gene expression in organoids.

Keywords:
Notch signalingoptogeneticsorganoidsegmentation clocksynthetic biology

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Area of Science:

  • Developmental Biology
  • Systems Biology
  • Synthetic Biology

Background:

  • The segmentation clock, involving oscillatory gene expression in the presomitic mesoderm (PSM), drives somite formation during vertebrate development.
  • Delta-Notch signaling synchronizes these oscillations at the population level, with its inhibition leading to somite fusion.
  • The precise mechanisms by which cell-cell signaling couples and synchronizes oscillatory gene expression remain incompletely understood.

Purpose of the Study:

  • To investigate how synthetic cell-cell signaling can induce synchronized oscillations in PSM organoids.
  • To elucidate the role of intracellular domains of synthetic ligands in cell-cell communication.
  • To determine if synthetic signaling can restore synchronized oscillations in cells lacking functional Delta-Notch signaling.

Main Methods:

  • Generation of PSM organoids.
  • Implementation of synthetic cell-cell signaling using designed ligand-receptor pairs.
  • Optogenetic assays to probe intracellular signaling dynamics.
  • Assessment of oscillatory gene expression and synchronization in manipulated PSM cells.

Main Results:

  • Synthetic cell-cell signaling successfully induced synchronized oscillations in PSM organoids.
  • Optogenetic experiments revealed the critical role of synthetic ligand intracellular domains in dynamic communication.
  • Oscillatory synthetic coupling restored synchronized gene expression in Delta-Notch signaling-deficient PSM cells.
  • Non-oscillatory synthetic coupling failed to restore synchronization.

Conclusions:

  • Ligand-receptor molecules play a crucial role in coordinating segmentation clock synchronization.
  • Synthetic cell-cell signaling provides a novel method to program temporal gene expression in organoids and artificial tissues.
  • This study offers insights into the fundamental mechanisms governing biological oscillations and tissue patterning.