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A new study suggests this developmental pathway is worthy of more scrutiny in future research into Fraser syndrome, a many-faceted and rare recessive genetic disease. In humans, a mutation in the gene FRAS1, which plays a role in skin epithelial formation during early development, has been linked to Fraser syndrome. A comparable version of the gene, fras1, in zebra fish is required for stable skeletal formation.

As reported in the journal Development, researchers modeled craniofacial symptoms related to hearing loss in Fraser syndrome using mutant zebra fish, focusing on an endodermal pouch (known as p1), which in humans forms the Eustachian tube.

Using tissue labeling and time-lapse microscopy, researchers found “a previously unrecorded, late-forming portion of the first pharyngeal pouch in the zebra fish,” says lead author Jared Coffin Talbot, who earned a doctoral degree from the University of Oregon and is now is a postdoctoral researcher at Ohio State University.

The newly seen component is a fras1-dependent “endodermal outpocket”—referred to in the paper as a late-p1. “If this homology can be taken as a guide, then endodermal pouching defects might underlie some ear defects in Fraser patients,” the researchers conclude.

“In fras1-mutant fish, some skeletal elements near late-p1 do not form properly during this time period,” Talbot says. “However, after this time period, two other skeletal elements that would have normally been separated by late-p1 fuse together in fras1 mutants that lack late-p1. We propose that in normal development late-p1 holds apart skeletal elements found fused in fras1 mutants.”

To test that idea, researchers in the lab of Charles B. Kimmel, professor emeritus of biology, added healthy epithelia tissue from wild-type zebra fish, into fras1-mutant embryos. Doing so allowed for normal facial development in the mutants.

“To my knowledge, the connection between skeletal development and Fraser syndrome deafness has not yet been made in mammals,” Talbot says. “The literature has been largely mute as to why skeletal defects are found in fras1 mutants; this is what made it an interesting topic to study, but it does make a direct zebrafish-human connection more difficult to make. We believe that the middle ear and Eustachian tube are the homologous structures to what we’re studying in zebra fish.”

Fraser syndrome is a poorly understood disorder that can affect multiple parts of the body, but the majority of cases involve the eyes. Canadian geneticist C.R. Fraser described the disease in 1962. The FRAS1 gene previously had been identified as an adhesive and signaling molecule in epithelial tissues. The new paper shows the gene also acts in epithelia to sculpt skeletal shape.

“Specifically, we learned that zebrafish fras1 acts in tissues homologous to the human ear canal to sculpt tissues homologous to the human middle ear,” Talbot said. “To our knowledge, the shape of middle ear bones has not been studied in Fraser syndrome patients, nor has the Eustachian tube. We suggest that these tissues in human Fraser patients may prove highly fruitful.”

Researchers from the University of Colorado Denver, the Institute of Molecular and Cell Biology in Singapore, and the University of Cologne in Germany contributed to the study.

More news from University of Oregon: http://uonews.uoregon.edu/