Figure 1: A light micrograph of a mouse embryo. RIKEN researchers have created synthetic molecular pathways that illuminate embryonic development. © ARTHUR CHIEN/SCIENCE PHOTO LIBRARY
Synthetic molecular pathways created by RIKEN researchers illuminate embryonic development and could help to advance research, drug development and clinical care1.
The development of an embryo is governed by an intricate array of cell signaling mechanisms, which transmit precise messages at specific times.
One notable example is the segmentation clock in embryos, which controls oscillatory signals and ensures the correct molecular messages are sent to form immature tissues that eventually go on to become bone and muscle.
But these complex mechanisms are poorly understood. RIKEN researchers have now discovered a new way to dissect segmentation clock signals, which promises to shed new light on embryonic development.
The team created synthetic molecular communication networks that simplify these pathways, providing new clues to how they operate.
"Our basic question was: how is the body constructed autonomously?" says Akihiro Isomura of the RIKEN Center for Brain Science. "We wanted to understand the communication codes between cells and how they are synchronized."
The team focused on the Delta-Notch pathway, which plays a key role in cell signaling. Delta is a signaling protein that binds to Notch, a receptor protein, to transmit these critical messages.
While Notch was thought to play a central role in synchronizing cell signals during early development, there has been little direct evidence for this because Delta-Notch is complex and difficult to study.
The team tackled the problem by developing synthetic Delta-Notch proteins to simplify analysis.
Notch has three interconnected domains: outside the cell, inside the cell membrane, and inside the cell itself.
By creating and rigorously testing different synthetic domains, the researchers developed pathways with minimal machinery for cell-to-cell communications. This approach made the Delta-Notch much easier to study and revealed new information about cell signaling.
"Previously, nobody knew the function of the domain inside the cell," says Isomura. "But we showed that it plays a key role in sending these oscillatory communication signals."
These synthetic tools helped the team control the segmentation clock to more rationally induce organoids-3D cellular structures that can mimic organs-from mouse embryonic stem cells. Organoids provide superior models to study development, test drugs, model disease and advance personalized medicine.
"Many labs are working to develop organoids, but they're running into barriers, such as the temporal signals needed to build tissues," notes Isomura. "Our study opens the way to control more complex cellular behaviors with synthetic signaling."
Akihiro Isomura (third right in second row) and Ryoichiro Kageyama (third left in first row) and co-workers have created synthetic molecular pathways that illuminate embryonic development and could advance research, drug development and clinical trials. © 2026 RIKEN
