Zebrafish should be known to many aquarium enthusiasts mainly because of their striking colour. However, the distinctive black and blue stripes, to which the animal owes its name, are formed only over time. On the other hand, its larvae are still more or less transparent eyelash size. Therefore, many developmental processes in their bodies can be observed under a light microscope. For this reason, it now serves as a model organism for research groups around the world.
“At the University of Bonn, for example, we are investigating how zebrafish repair defective nervous tissue,” explains Professor Benjamin Odermatt of the Institute of Anatomy at the University Hospital Bonn. “We are also interested in this because many of the genes involved in this process are also found in a similar form in humans.” In principle, factors that promote these repair genes in fish could also act in humans. However, the differences between the genetic makeup of fish and humans are often significant. Therefore, caterpillars are sometimes of limited use in the search for new drugs.
Replacing the fish gene with a human gene
“So we took a different approach,” explains Prof. Dr. Evi Kostenis from the Institute of Pharmaceutical Biology at the University of Bonn. “For a human gene known to play a role in neuronal repair, we looked for its counterpart in zebrafish. Then we excised that counterpart in the fish and replaced it with the human version.” The new genetic material took over the function of the original zebrafish gene. “If we now find a substance that promotes repair processes in fish using the human gene, there is a good chance that this will also be the case in humans,” says the scientist, who is also a member of the Interdisciplinary Research Area. “Life and Health” at the University of Bonn.
The researchers showed that this variant works in their experimental study on what’s called the GPR17 receptor. In humans, its overactivity can lead to diseases such as multiple sclerosis (MS). Neurons communicate by electrical signals. Its extensions are surrounded by a kind of insulating layer, a fat-like substance called myelin. It prevents short circuits and significantly speeds up the transmission of stimuli. This protective covering is produced by specialized cells called oligodendrocytes. These are similar to a microscopic octopus: many long arms extend from the cell body, consisting mostly of myelin. Like insulating tape, these wrap around the processes of neurons during brain development. Usually, the protective layer lasts a lifetime.
The insulating tape dispenser remains in an immature state
In the case of multiple sclerosis, the body’s immune system destroys the myelin layer. This results in neurological disturbances, for example in speech, vision or walking. But there is usually a supply of immature oligodendrocytes in the brain for repair work. When damage occurs, they ripen and repair the hole. In the case of multiple sclerosis, this mechanism is disrupted – many cell isolation tape donor cells remain in their immature state. The GPR17 receptor appears to bear the main blame for this: if it is activated by a molecular signal, it slows down the maturation of oligodendrocytes.
“Zebrafish also contain the GPR17 receptor,” explains Dr. Jesus Gomesa, who led the study with Costines and Dermatt. “There it also regulates the number of mature oligodendrocytes.” The researchers have now replaced part of the receptor gene with its human counterpart – the structure responsible for receiving molecular signals. “We were able to demonstrate that this new mosaic gene functions normally in fish larvae,” Gomeza says. The test-tube molecule that inhibits the human GPR17 receptor also increases the formation of mature oligodendrocytes in the modified fish.
In the search for new active ingredients, the materials are first tested in cell cultures. Only the most promising individual candidates are then tested in mice or other animal models. But even if they work there, the tests on humans often end up realistically. Benjamin Odermatt explains that “humanized zebrafish larvae allow screening of many substances quickly, with a high chance of success, because the target genes originate from humans.” “In our view, this is a very promising avenue for drug development.”