Researchers recreate the periodic structure of spinal development without biological clocks

One of the most dramatic phases of fetal development occurs when previously unstructured collections of rapidly dividing precursor cells begin to form the backbone of the embryo.

When this process goes well, it lays a solid foundation for the many other development steps that follow. When this is not the case, the growth defects that follow can be serious.

Now, a research team from Cincinnati Children’s and the University of Cincinnati has discovered how a set of segmentation clock genes instruct the rate of spinal cord formation. Clock gene mutations lead to birth defects in humans called congenital scoliosis. The team’s findings open wider doors to a new wave of basic science research that may one day enable interventions when clock genes throughout our bodies become out of sync.

Details were posted online on December 14, 2022, at Nature.

Repair a broken watch

In animals with spines (including humans), the growing embryo forms soft segments called somites that later develop into bony vertebrae. These somites also give rise to the formation of ribs and related back muscles and skin.

A research team led by first author M. Fethullah Simsek, Ph.D., and senior author Ertuğrul Özbudak, Ph.D., both from Cincinnati Children’s Division of Developmental Biology, identified a decrease in cell signaling molecule that causes the formation of a new segment. The work involved using genetically modified zebrafish to detect key signaling variations. Using what they learned about signaling, the research team was able to biochemically induce segment formation in zebrafish at will, despite the fact that the fish had been engineered to lack the clock genes that normally control this process.

The latest work builds on the team’s widely shared findings on how co-expressed gene pairs help drive the timing of body segmentation. That study was published on December 23, 2020 in Nature.

“We believe that this study will be important for researchers in biology, bioengineering, and computational biology,” says Özbudak. “Understanding how cells prepare to form a segment boundary

in a specific location could help researchers understand the origins of other malformations that can occur during fetal development in addition to early spinal formation.”

The team confirmed that the signaling molecules they studied are conserved from fish to humans. However, much more research will be required to determine whether the interventions that helped correct spinal malformations in zebrafish can be translated to humans.

A hopeful long-term application of this study may be that it provides guidance for trying to grow segmented tissues (such as the spine and fingers) in the laboratory, suggesting a new front for organoid development.

“Broad animal species, from centipedes and beetles to humans, segment their bodies sequentially. While the molecules involved differ dramatically between species, our study indicated that sequential segmentation can still be achieved as long as a clock ticks its periodicity on a gradient of morphogen,” says Özbudak. . “We anticipate that our findings will inspire the engineering of repetitively organized tissues. on plate using pulsatile perturbation of signaling gradients”.

Next steps

The next step is to discover the molecular link between the segmentation clock and its downstream signaling pathway.

“We are hopeful that discovering the molecular link missing so far could be clinically relevant and targetable,” says Özbudak.