Northwestern Medicine investigators have identified novel mechanisms regulating the development of the spinal column during embryonic development, findings that could inform new treatments for congenital scoliosis and other related birth defects, according to a recent study published in Nature Communications.
The spinal column of all vertebrate species, including humans, is divided into segments, or vertebral discs, which give the spine both flexibility and mobility.
During early embryonic development, these discs develop from specialized cells called somites and are sequentially “sliced” into separate discs, a process driven by a biological clock called the vertebrate segmentation clock.
“It’s a sequential segmentation and periodic segmentation, and the clock refers to some genes that express RNA and proteins. These expressions are not always occurring constantly, it happens in oscillations, like waves,” said Ertugrul Özbudak, PhD, the Robert Laughlin Rea Professor of Cell Biology in the Department of Cell and Developmental Biology and senior author of the study.
Each somite cell contains two clock proteins, Her1 and Her7, which help regulate the vertebrate segmentation clock. In parallel, DeltaC and DeltaD proteins activate the Notch signaling pathway, which in turn activates the transcription of clock genes in neighboring presomitic cells.
Mutations in these pathway genes result in vertebral segmentation defects in humans, such as congenital scoliosis.
“There’s a collective action. Hundreds of cells synchronously produce and degrade these molecules and that requires cell-to-cell communication,” Özbudak said.
Previous work had suggested that only one of these ligands, DeltaC, contributed to the transcription of segmentation clock genes.
To better understand how DeltaC and DeltaD influence the transcription of Her1 and Her7 vertebrate segmentation clock genes, Özbudak’s team performed advanced imaging in different genetic backgrounds of zebrafish embryos.
Surprisingly, they found that DeltaD was not only functional but also that Notch signaling promotes the transcription of both DeltaC and DeltaD genes.
“DeltaC oscillates and immediately contributes to synchronization. DeltaD does not oscillate but elevates the levels of the target gene so they can be capable of oscillating and synchronization,” Özbudak said.
The findings will help improve the understanding of why these two genetic mutations give rise to congenital spine abnormalities and inform future work to identify new therapeutic strategies, Özbudak said.
“In the near future, we are aiming to assess the contributions of other transcription regulators and other cell signaling mechanisms,” Özbudak said.
Eslim Esra Alpay, a lab technician in the Özbudak laboratory, was lead author of the study.
This work was funded by National Institutes of Health grant R35GM140805.
