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Researchers from Radboud University Medical Center and Radboud University developed a zebrafish model for FOXE1-related craniofacial malformations that recapitulates several phenotypical aspects of patients including hypothyroidism. They also show a clear gene-environment interaction as ethanol aggravates the phenotype.
Many diseases are rooted in genetic defects, but the expression and severity of symptoms differs between individuals. For example, mutations in genes involved in pathways controlling skeletal development are associated with craniofacial malformations such as cleft palate. At the same time, environmental factors such as drug use, smoking, drinking and other lifestyle habits during pregnancy increase the risk of congenital malformations. Apparently, it is the interplay between genes and environmental factors that shapes craniofacial development.
FOXE1 mutations in humans are associated with cleft palate and hypothyroidism. This type of congenital malformations is known to be strongly influenced by environmental factors, but animal models to investigate this are scarce. Researchers of Radboudumc and Radboud University developed a foxe1 mutant zebrafish demonstrating mineralization defects in larvae. In the present study, they investigate the thyroid status and skeletal phenotype of adult foxe1 mutants as well as the influence of ethanol on the phenotype. Maternal ethanol exposure during fetal development causes fetal alcohol spectrum disorders and fetal alcohol syndrome, which include abnormal craniofacial features. As in patients, the mutant adult fish show mineralization defects and craniofacial malformations. The mutant fish further show signs of hypothyroidism, another clinical feature. Then the researchers investigated whether ethanol exposure increases the risk of developing craniofacial malformations in foxe1 mutant larvae. Upon exposure to ethanol, they found an increased incidence of developmental malformations and marked changes in gene expression patterns of cartilage markers, apoptotic markers, retinoic acid metabolism, and tissue hypoxia markers. Taken together, this study shows that the foxe1 mutant zebrafish recapitulates phenotypes associated with FOXE1 mutations in human patients and a clear foxe1-ethanol interaction. The versatile zebrafish model can be used to screen for possible gene-environment interactions in the etiology of craniofacial malformations. These data can improve the prevention of these malformations.
The joint team of Radboudumc (Department of Dentistry) and Radboud University (Department of Plant & Animal Biology) is studying the role of genetic and environmental factors in craniofacial malformations in zebrafish models. In Radboudumc, this research is part of the program Orofacial Health of the Radboud Institute for Medical Innovation. In Radboud University, it belongs to the Radboud Institute for Biological and Environmental Sciences. This article is part of a recent PhD thesis: Zebrafish skeletal development; Genetic and environmental factors underlying craniofacial malformations, by Sophie Raterman.
The article is linked to research program Orofacial health
About the publication
Raterman ST, Wagener FADTG, Zethof J, Cuijpers V, Klaren PHM, Metz JR, Von den Hoff JW. Foxe1 mutant zebrafish show indications of a hypothyroid phenotype and increased sensitivity to ethanol for craniofacial malformations. Dev Dyn. 2025 Mar;254(3):240-256. doi: 10.1002/dvdy.745. Epub 2024 Oct 3. PMID: 39360443;PMCID: PMC11877993.
