Tissue dynamics provide clues to human disease

April 03, 2020

Segmentation clock

Our vertebral column is a highly repetitive structure - 33 vertebrae from top to bottom. This arrangement is created in the embryo by the sequential formation of a long row of structures called somites (see image), which later give rise to the vertebrae and ribs. This periodic pattern of somites is created by a group of genes known as the segmentation clock. Molecular interactions within the cell cause the expression of these genes to oscillate, with gene activity rising and falling in a regular pattern over time (see movie below). For each oscillation, another somite is formed. Errors in this segmentation clock can cause hereditary disorders of the vertebrae, such as the rare condition spondylocostal dysostosis (SCD).

The dynamics of the human segmentation clock and related diseases cannot be studied directly in human embryos, so EMBL Research Scientist Mitsuhiro Matsuda and collaborators tried to create a system for studying this process in the lab. They created cell lines that each lacked a gene thought to be the causative mutation of SCD - which can be caused by any of several genes - in different patients. They cultured these cells to create simplified versions of an embryo that show many of the same characteristics. While cells lacking a gene called HES7 failed to show oscillations, cells lacking the genes DLL3 and LFNG surprisingly showed intact oscillations. However, despite oscillations occurring in these cell lines at the single-cell level, they did not properly coordinate across the tissue to form synchronised collective oscillations or travelling waves of gene activity.

Further tests

These experiments demonstrated that the culture system the scientists has created could reveal SCD mutations that had been engineered into otherwise healthy cells. But what about testing patients' cells directly? They established a new cell line from a patient with a mutation in DLL3, and tested it in vitro. As expected, this cell line failed to show travelling waves. To provide the strongest evidence that the DLL3 mutation was the cause, the researchers used the gene editing tool CRISPR-Cas9 to correct the patient's mutation. This restored the normal synchronisation of the segmentation clock in the in vitro tissue, proving that this specific mutation was responsible.

"The segmentation clock, the mechanism underlying the periodic structures of the vertebral column, has been recapitulated in vitro. We also succeeded in evaluating two important properties of the segmentation clock separately: oscillation and synchronisation," says EMBL group leader Miki Ebisuya. "HES7, DLL3, and LFNG were already known as causative genes of SCD. But, for many SCD patients, the causative genes are still unknown. Our next goal is to identify a novel causative gene of SCD by using our newly established in vitro model."
-end-


European Molecular Biology Laboratory

Related Genes Articles from Brightsurf:

Are male genes from Mars, female genes from Venus?
In a new paper in the PERSPECTIVES section of the journal Science, Melissa Wilson reviews current research into patterns of sex differences in gene expression across the genome, and highlights sampling biases in the human populations included in such studies.

New alcohol genes uncovered
Do you have what is known as problematic alcohol use?

How status sticks to genes
Life at the bottom of the social ladder may have long-term health effects that even upward mobility can't undo, according to new research in monkeys.

Symphony of genes
One of the most exciting discoveries in genome research was that the last common ancestor of all multicellular animals already possessed an extremely complex genome.

New genes out of nothing
One key question in evolutionary biology is how novel genes arise and develop.

Good genes
A team of scientists from NAU, Arizona State University, the University of Groningen in the Netherlands, the Center for Coastal Studies in Massachusetts and nine other institutions worldwide to study potential cancer suppression mechanisms in cetaceans, the mammalian group that includes whales, dolphins and porpoises.

How lifestyle affects our genes
In the past decade, knowledge of how lifestyle affects our genes, a research field called epigenetics, has grown exponentially.

Genes that regulate how much we dream
Sleep is known to allow animals to re-energize themselves and consolidate memories.

The genes are not to blame
Individualized dietary recommendations based on genetic information are currently a popular trend.

Timing is everything, to our genes
Salk scientists discover critical gene activity follows a biological clock, affecting diseases of the brain and body.

Read More: Genes News and Genes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.