Researchers pause vertebral segmentation clock

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Waves of vertebrae-building signals pulse outward in mouse cells mimicking a developing embryo. Video: Pourquié lab

Researchers have been able to halt and restart the “ticking” of the vertebral segmentation clock in mouse cells. They speculate that this discovery could contribute to the understanding of spinal defects like scoliosis.

The spine is made up of a series of similar vertebrae. This repetitive arrangement is formed in developing embryos by a so-called segmentation clock. As the segmentation clock “ticks”, a vertebra starts to form.

This clock was discovered by Oliver Pourquie’s Harvard Medical School (Cambridge, USA) laboratory 20 years ago. Now, the group have reconstituted a stable version of this clockwork for the first time using mouse cells in a petri dish.

The research was published in Cell.

The team’s insights not only illuminate normal vertebrate development, but also could lead to improved understanding of human spinal defects such as scoliosis, says Pourquié. Pourquié is also the HMS Frank Burr Mallory professor of Pathology at Brigham and Women’s Hospital (Boston, USA) and a principal faculty member of the Harvard Stem Cell Institute (Cambridge, USA).

Understanding the segmentation clock

The researchers found that the segmentation clock lies quiescent in individual embryonic cells that give rise to the vertebrae. When the cells reach a critical mass, it clicks on all at once.

The team further discovered that the clock is controlled by two signals—Notch and Yap—that are sent and received by these cells.

Notch starts the clock ticking by triggering cellular oscillations that release instructions to build structures that will ultimately become vertebrae.

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,” says Pourquié, then Notch is needed to start the clock. And, if Yap levels are high, even a lot of Notch will not convince the clock to tick. This is an excitability threshold.

“If you stimulate the system a little, nothing happens. But if you stimulate it a little more and cross the threshold, then the system has a very strong response,” explains Pourquié.

The team theorise that the segmentation clock works like other excitable biological systems that require certain thresholds to be met before sparking an action. This is similar to the firing of neurons in the brain and the travelling of calcium waves across heart cells.

“There are probably similarities in the underlying circuits,” Pourquié adds.

The researchers were surprised to find that they could stop and restart the segmentation clock in several ways. They could physically halt its mechanism by separating and reaggregating the cells, and chemically stop it with a Yap-blocking drug.

“For many years, we have been trying to understand the clockwork underlying these oscillations,” says Pourquié. “Now we have a great theoretical framework to understand what generates them and to help us make and test more hypotheses.”

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