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August 1, 2012--------News Archive Return to: News Alerts


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Fraser Syndrome Hearing Loss and Zebra Fish

Study of the earliest formation of cartilage in the mouths of mutant zebra fish, may have given a look at a genetic defect linked to Fraser syndrome deafness in humans

Fraser syndrome is a many-faceted and rare recessive genetic disease, which plays a role in skin epithelial formation during early development. In humans, a mutation in the FRAS1 gene, has been linked to Fraser syndrome. A comparable version of the fras1 gene, in zebra fish, is required for stable skeletal formation.

Reporting in the Aug. 1 issue of the journal Development, researchers identified a development pathway worthy of future investigation.

In the study - done at the University of Oregon's Institute of Neuroscience - researchers modeled craniofacial symptoms related to hearing loss in Fraser syndrome using mutant zebra fish. Their research focused on a zebra fish endodermal pouch (known as p1), which in humans forms the Eustachian tube.

Labeling tissue and using time-lapse microscopy, the research team found "a previously unrecorded, late-forming portion of the first pharyngeal pouch in the zebra fish," said lead author Jared Coffin Talbot, now a postdoctoral researcher at Ohio State University.

The newly observed zebra fish pouch, researchers wrote, 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," they conclude.


"In fras1-mutant fish, some skeletal elements
near late-p1 do not form properly.
However, after this
[early] time period,
two other skeletal elements that normally
would have 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."

Jared Coffin Talbot, Ph.D.


To test that idea, the 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.

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 homologous structures to what
we're studying in zebra fish."

Jared Coffin Talbot, Ph.D.


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.

Talbot: "Specifically, we learned that zebrafish fras1 acts in tissues homologous to the human ear canal to sculpt tissues homologous to the human middle ear. 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."

Co-author John Postlethwait, a UO biologist, says his students often are intrigued when he shows them the similarities in the development of fish gills and their own Eustachian tube.

Postlethwait: "They know about what happens to their ears when they go up in an airplane, but are surprised at the evolutionary development of that ear-popping sensation."


Another part of the new study also may provide insights
into the many other faces of Fraser syndrome:
partial webbing of fingers or toes;
kidney abnormalities; genital malformations;
and complete fusion of the eyelids.


Talbot: "We carefully controlled for genetic and environmental factors by comparing the left and right sides of inbred zebrafish fras1 mutants raised in petri dishes. When we did this, we found a remarkable degree of variation in skeletal defects. Our results appear to support the hypothesis that the degree of Fraser symptoms is to some extent determined by chance."

"These findings open a new window on the underlying mechanisms of this rare disorder. Basic research in genetics at the UO using zebra fish as a tool reveals the fundamental dynamic processes that undergird development and helps to explain how it goes awry in medical conditions." says Kimberly Andrews Espy, vice president for research and innovation.

Co-authors with Talbot, Kimmel and Postlethwait are: former UO doctoral student Macie B. Walker, now at the University of Colorado Denver; Thomas J. Carney of the Institute of Molecular and Cell Biology in Singapore; Matthias Hammerschmidt of the University of Cologne in Germany; undergraduate UO student Tyler R. Huycke, now a technician in Kimmel's lab; Yi-Lin Yan and Ruth A. BreMiller, who work in Postlethwait's lab; high school intern Linda Gai; and April DeLauier, a postdoctoral researcher in the UO Institute of Neuroscience.

The National Institutes of Health supported the research (grants R01DE013834, U01DE020076, P01HD022486, T32HD007348 and T32GM007413). Hammerschmidt was supported by a grant from the German Research Foundation.

About the University of Oregon
The University of Oregon is among the 108 institutions chosen from 4,633 U.S. universities for top-tier designation of "Very High Research Activity" in the 2010 Carnegie Classification of Institutions of Higher Education. The UO also is one of two Pacific Northwest members of the Association of American Universities.

Sources: Jared Coffin Talbot, postdoctoral researcher, Ohio State University, 614-292-8084, talbot.39@osu.edu; John H. Postlethwait, professor of biology, UO, 541-346-4538, jpostle@uoregon.edu

Links:
UO Institute of Neuroscience: http://www.neuro.uoregon.edu/

About Charles Kimmel: http://www.neuro.uoregon.edu/ionmain/htdocs/faculty/kimmel.html

About John Postlethwait: http://uoneuro.uoregon.edu/ionmain/htdocs/faculty/postlethwait.html

Follow UO Science on Facebook: http://www.facebook.com/UniversityOfOregonScience

Original article: http://uonews.uoregon.edu/archive/news-release/2012/7/study-zebra-fish-mouth-formation-may-speak-fraser-syndrome-hearing-loss