Reengineering Somite Segmentation without a Biological Clock

Discovery seen as important for biomedical engineering and developmental biology research involving disruptions to early embryonic development.

One of the most dramatic phases of embryonic development occurs as previously unstructured collections of rapidly dividing precursor cells begin forming the embryo’s spinal column. In animals with spines (including humans), the growing embryo forms soft segments called somites that later develop into vertebral column and associated ribs, skeletal muscles and skin. Thus, somitogenesis establishes the segmental pattern of the vertebrate body axis. A molecular segmentation clock in the precursor cells sets the pace of somite formation. Mutations of the segmentation clock genes lead to birth defects in humans called congenital scoliosis. However, how cells are primed to form a segment boundary at a specific location was unclear. Özbudak lab developed precise reporters for the segmentation clock and double-phosphorylated Erk (ppErk) gradient in zebrafish. They showed that the segmentation clock drives segmental commitment by periodically lowering ppErk, therefore projecting its oscillation onto the ppErk gradient. The team was able to biochemically induce segment formation in zebrafish at will even though the fish had been engineered to lack the clock genes that normally control this process. Thus, they showed that pulsatile inhibition of the ppErk gradient can fully substitute for the role of the clock for sequential somite segmentation. The clock functions upstream of ppErk, which in turn enables neighboring cells to discretely establish somite boundaries in zebrafish. The team’s findings open doors wider to a new wave of basic science research that may someday allow interventions when the clock genes disfunction. One hopeful longer-term application of this study may be that it provides guidance for attempting to grow segmented tissues (like the spine and digits in the hand) in the lab, suggesting a new front for organoid development.

Details were published online in Nature in 2023.