Breakthroughs in Spinal Column Development from Zebrafish

Scientists at Northwestern Medicine have uncovered new insights into how the spinal column develops in vertebrates, as outlined in a study published in Developmental Cell. While the role of oscillating proteins and intercellular signals in vertebral segmentation has been known, the exact mechanisms have remained unclear.

The findings offer a clearer understanding of spinal column development and may lead to potential therapies for congenital scoliosis, according to Ertuğrul Özbudak, Ph.D., the senior author and Robert Laughlin Rea Professor of Anatomy. Özbudak’s previous work identified two crucial molecular components involved in vertebral segmentation: one acting as a "clock" and the other as a "knife."

The "clock" controls the frequency at which somites, the precursors to the vertebral column, form, while the "knife" determines the placement of boundaries between somites. Özbudak’s research shows that these two molecular pathways are fundamental in defining segment borders and their numbers.

In this study, the researchers focused on zebrafish to explore how these pathways interact. Using bimolecular fluorescence complementation assays, they observed that the "clock" proteins Her1 and Her7 directly interact with the phosphatase proteins Dusp4 and Dusp6.

The team then inhibited the activity of the Dusp proteins and found that the normal oscillation of phosphorylated ERK kinase was disrupted, resulting in improper somite boundaries. This revealed the molecular link between the segmentation clock and ERK kinase, which controls boundary positions.

According to Özbudak, these transcription factors have a new function that was previously unknown: they physically interact with Dusp phosphatases, stabilizing them and inhibiting ERK kinase activity. This interaction plays a key role in vertebral column segmentation.

The study highlights how the interaction between these proteins forms the blueprint for vertebrate body structures. It also suggests that these pathways could be targeted with pharmaceutical treatments, potentially aiding in the development of therapies for congenital scoliosis and providing greater insight into the causes of birth defects.