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Research into how stem cells become cartilage, bones, or teeth in the developing faces of zebrafish could one day lead to advances in regenerative medicine.

"Being a bony vertebrate like us, the developmental and genetic control of facial development in zebrafish is highly conserved with that in humans. This means that we can use the powerful genetics of zebrafish to make models of human craniofacial birth defects in this rapidly developing, transparent species," Gage Crump, one of the study's authors, told ALN.

A new study, published in Development, examined the role of a key family of genes, called "Forkhead-domain transcription factors," or Fox to learn more about its role in facial development.

The researchers studied zebrafish bred to lack Fox-C or Fox-F genes. This allowed them to pinpoint what each gene specifically does in the development of cartilage, bones, or teeth.

"For this project, we deleted more than 10 FOX genes and examined animals with different combinations of missing FOX genes. In so doing, we uncovered that FOX genes help determine where in the face particular cartilages, teeth, and bones form - thus establishing a “FOX code” for the facial skeleton," Crump said.

Fish lacking Fox-C did not form cartilage in their upper faces, while the animals without Fox-F had difficulties with jaw development, cartilage in the middle of their faces, and teeth.

Further research revealed that Fox-C and Fox-F also play an important role in assisting the gene Sox9 in the development of cartilage throughout the embryo.

Similar findings have been made in laboratory mice lacking Fox genes. This suggests that the Fox genes play a crucial role in the facial development of many vertebrates, including humans.

"The homolog of one of the genes we have been studying - FOXC1 - is mutated in a human birth defect called Axenfeld-Rieger Syndrome. This syndrome is characterized by many defects in the face, including the eye, teeth, and bony skeleton. Homologs of other genes we study, such as FOXF1 and FOXF2 - have also been implicated in cleft palate. Our work helps to uncover the developmental basis for defects in Axenfeld-Rieger and other craniofacial syndromes," Crump added.

"In addition, our work shows how the combination of FOX and SOX transcription factors can robustly induce cartilage formation. This may allow us to better make cartilage in vitro for regenerative medicine applications."

ALN also spoke to Gage Crump about the connection between fish jaws and human hearing loss and what the zebrafish can tell us about jaw development.

Image: Skeletal staining of the lower face of a zebrafish, with cartilage in blue, and bones and teeth in red. Credit: Image by Pengfei Xu/Crump Lab/USC Stem Cell

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