In a paper published last week in Cell, Harvard Medical School genetics professor Olivier Pourquié, whose lab discovered the segmentation clock 20 years ago, and colleagues report that they used a mouse in vitro system to reconstitute a stable version of this clockwork, leading to several new discoveries about where the clock is located, what makes it tick, and how the vertebral column takes shape.
The team's insights not only illuminate normal vertebrate development but also could lead to improved understanding of human spinal defects, said Pourquié, who is also the Harvard Medical School Frank Burr Mallory Professor of Pathology at Brigham and Women's Hospital and a principal faculty member of the Harvard Stem Cell Institute.
The researchers found that the segmentation clock lies quiescent in individual embryonic cells that give rise to the vertebrae, then clicks on all at once, collectively, when the cells reach a critical mass. In addition, they found that the clock is controlled by two signals, Notch and Yap.
On its own, they found, Notch starts the clock ticking by triggering cellular oscillations that release instructions to build structures that will ultimately become vertebrae. And the cells' Yap chatter determines the amount of Notch required to activate the segmentation clock. If Yap is very low, then the clock runs on its own. If Yap levels are "medium," said Pourquié, then Notch is needed to start the clock. And if Yap levels are high, even a lot of Notch won't convince the clock to tick.
The researchers theorize that the segmentation clock works like other excitable biological systems that require certain thresholds to be met before sparking an action, such as neurons firing and calcium waves traveling across heart cells.
"For many years, we have been trying to understand the clockwork underlying these oscillations," said Pourquié. "Now we have a great theoretical framework to understand what generates them and to help us make and test more hypotheses."
Image: Screenshot from video of waves of vertebrae-building signals pulsing outward in mouse cells mimicking a developing embryo. Image courtesy of Pourquié lab.