Fishing for improvement The role of the zebrafish in cleft lip research

23 June 2026

Most people know someone with a cleft condition, such as comedian Jan Jaap van der Wal or rapper Snelle. But how does a cleft actually develop? And how can we best support those affected? Cell biologist Hans Von den Hoff from Radboudumc is investigating these questions. 'The zebrafish has a characteristic that makes it particularly suitable for this type of research.'

A baby’s face begins to take shape in the very first weeks of pregnancy. Sometimes even before a woman knows she is pregnant. During this early stage, different parts of the face grow towards each other. In most cases, this process proceeds without any problems. However, sometimes not all structures fully fuse together, leaving a gap.

Such a congenital opening in the face is called a cleft. The term comes from Greek and literally means ‘split’. Each year, around three hundred babies are born with a cleft in the Netherlands. There are considerable variations: the split can affect the upper lip, the jaw, and/or the palate. In some cases, it even extends toward the back of the mouth.

A cleft is therefore caused by facial structures not properly fusing during pregnancy. However, why this occurs in some babies is not yet fully understood. 'Together with fellow researcher Frank Wagener, I conduct extensive research into this', says cell biologist Hans Von den Hoff.

Tiny fish

For their research, Von den Hoff and Wagener use a surprising animal: the zebrafish. This small tropical freshwater fish closely resembles humans during early development and, like us, can develop a cleft. 'Moreover, the zebrafish has another feature that makes it highly suitable for research', Von den Hoff explains. 'Its embryos are transparent. This allows us to follow development step by step and exactly see how different cells work together to form the head and face.'

We know that a cleft can sometimes result from a mistake in genetic material: the DNA. However, how such a small genetic change leads to a facial abnormality remains unclear. To better understand this, Von den Hoff’s team introduces a similar mutation into the DNA of zebrafish. At the same time, they label the cells that form the head and face with a fluorescent marker.

'Under the microscope, we then see all these tiny green dots moving', Von den Hoff explains. 'Those are the cells. They allow us to track whether there are enough cells, whether they reach the right location, and whether they develop normally. This helps us understand how a cleft forms and how we might one day guide these cells to prevent it.'

Alcohol in the aquarium

Interestingly, children with the same genetic mutation can still develop very different forms of clefts. This suggests that environmental factors also play a role, such as nutrition, vitamins, or medication during pregnancy.

Von den Hoff’s group also studies this using zebrafish. For example, they found that when a small amount of alcohol is added to the water, zebrafish with a specific genetic mutation develop a more severe cleft than fish not exposed to alcohol. As with many genetic conditions, heredity and environment appear to reinforce each other.

By better understanding this interaction, Von den Hoff and his colleagues hope to eventually prevent clefts, for instance, through targeted medication and improved guidance during pregnancy. 'It would be wonderful if we could reduce the number of babies born with a cleft in the future.'

In the picture: celbiologist Hans Von den Hoff.

Scarring

Nevertheless, there will always be children born with a cleft. Fortunately, the condition can be treated effectively. This usually involves multiple surgeries, for example, closing the lip and palate shortly after birth, and correcting the jaw when the child is around nine years old. Most children also receive speech therapy to support language development and orthodontic treatment to ensure proper dental and jaw alignment.

A major issue that arises from these surgeries is scar tissue. This can disrupt facial growth and cause speech problems, especially when scars form in the soft palate. This area contains muscles that are essential for proper speech. 'And these speech problems are often what children with a cleft find most difficult', says Von den Hoff.

Cultured cells

That is why he is searching for ways to reduce scarring after cleft surgery. 'We do this by growing muscle cells in a culture dish', he explains. 'We then add fibroblasts to these muscle cells, a type of cell that plays an important role in scar formation. Next, we test whether certain substances can inhibit the activity of these fibroblasts.'

'If that works, I would like to collaborate with fellow researcher Willeke Daamen to incorporate such a substance into fibrin glue', Von den Hoff continues. 'This special glue is already used by surgeons to close wounds. By applying it combined with the inhibitory substance during soft palate repair, we may be able to limit scar tissue formation. This would allow the muscles to move more freely, and hopefully reduce speech difficulties later in life.'

This approach is not only promising for children with a cleft. It could also be valuable for other conditions in which scar tissue forms in muscles, such as in patients with severe burns or those who have undergone surgery for cancer. 'Hopefully, this means we can not only better help children with clefts, but other patients as well', Von den Hoff concludes.

About the research

Von den Hoff conducts his research using zebrafish in collaboration with the zebrafish facility of Radboud University, led by Juriaan Metz, Assistant Professor of Plant and Animal Biology. In addition, he works closely with the patient organization Schisis Nederland, through which they contribute to greater knowledge and understanding of cleft lip and/or palate.

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