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August 1, 2012

Researcher's fish-eye view could offer insights for human vision

Zeran Li

Zeran Li
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WEST LAFAYETTE, Ind. - A Purdue University student's research project related to zebrafish eye development could lead to a better understanding of vision problems that affect billions of people worldwide.

Zeran Li, as an undergraduate student in biological sciences, led a research team that uncovered an enzyme's role in the regulation of eye size in the fish. If the enzyme's role is similar in human eyes, it could be relevant to human vision problems, such as nearsightedness and farsightedness.

"New insights into the process of eye-size control in zebrafish may help our understanding of the regulation of eye size in humans," said Li, who has since graduated and is pursuing a doctorate in neuroscience at Washington University. "Vision problems occur when the size or shape of the eye changes, and what causes this is unclear. Perhaps this research will lead to a better understanding of this mechanism and the discovery of a new treatment for these problems."

These vision problems, called refractive errors, occur because the physical length of the eye from the cornea to the retina is different from the optical length. If an eye is too long or too short, light is focused in front of or behind the retina and vision is blurred, she said.

Refractive errors affect 3.8 billion people worldwide, according to the International Center for Eye Education.

Li worked in the laboratory of Yuk Fai Leung, a Purdue assistant professor of biological sciences. Leung oversaw the research and guided the team, but credits the two undergraduate students in his lab for the idea.

"The inspiration for this study came from the undergraduate students," he said. "Their observations and interpretations helped shape our current focus and allowed us to make this discovery. I'm very proud of the scientists they are becoming."

The findings are detailed in a paper in PLoS ONE. In addition to Li and Leung, paper co-authors include Purdue undergraduate student Devon Ptak, postdoctoral researchers Liyun Zhang and Wenxuan Zhong, and continuing lecturer Elwood Walls.

Zebrafish are used as a model to study development and growth problems. The zebrafish, which are named for their naturally occurring black stripes, must be made transparent to enable the careful observation and imaging necessary for the research. The most common way to achieve this transparency is to treat zebrafish embryos with a chemical called phenylthiourea that blocks the formation of black pigment, he said.

Li had previously observed that zebrafish embryos treated with the chemical have smaller eyes than untreated fish, and found that in addition to blocking pigmentation, the chemical inhibits thyroid activity.

The thyroid produces hormones that regulate metabolism and influence growth, and it was thought that a general suppression of the thyroid hormone could be causing the reduction in eye size. Li theorized that phenylthiourea might suppress thyroid hormone production because it shares the same structure as a known thyroid hormone inhibitor. She tested the effects of several different inhibitors and found that not all had the same effect on eye growth. Only those that halted production of the enzyme thyroid peroxidase resulted in smaller eye size.

"If thyroid peroxidase has a specific role in the regulation of eye growth, it would be logical for it to express in the eye," Leung said. "Perhaps a localized manipulation of its activity in the eye could be used as a strategy to correct some vision problems. Of course, first we must learn much more about how it regulates eye size."

The findings also serve as a warning of the potential changes phenylthiourea may have on zebrafish - a widely used animal model - that could affect research results, he said.

"Our findings and others have shown that phenylthiourea can affect various aspects of physiology, so the results obtained from fish treated with it may not truly reflect what is going on inside the embryo," Leung said. "One should be cautious in interpreting their findings after phenylthiourea treatment. This discovery highlights the need to find a new way to remove pigmentation."

Leung's group attempted to find an alternative inhibitor for pigmentation, but all caused physiological problems and none were as efficient as phenylthiourea, he said.

The team plans to further investigate the relationship of thyroid peroxidase and thyroid hormone on eye growth and development.

Leung said the team also is analyzing the effects of traditional Chinese medicines considered good for vision using fish models of human retinal degeneration.

"Hopefully our efforts will expedite the discovery of novel treatments for human eye diseases," he said.

Li and Ptak received national Sigma Xi awards for vision research. Li also was a recipient of a Sandy and Zippy Ostroy Research Experience for Undergraduates Award and a Dr. William H. Phillips Undergraduate Research Internship. In addition to those awards, this research was funded by grants from the National Science Foundation and U.S. Department of Energy.

Writer: Elizabeth K. Gardner, 765-494-2081, ekgardner@purdue.edu

Sources: Zeran Li, zeranli@wustl.edu

                Yuk Fai Leung, 765-496-3153, yfleung@purdue.edu 

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Related information:

Link to research paper



ABSTRACT

Phenylthiourea Specifically Reduces Zebrafish Eye Size

Zeran Li, Devon Ptak, Liyun Zhang, Elwood K. Walls, Wenxuan Zhong, Yuk Fai Leung

Phenylthiourea (PTU) is commonly used for inhibiting melanization of zebrafish embryos. In this study, the standard treatment with 0.2 mM PTU was demonstrated to specifically reduce eye size in larval fish starting at three days post-fertilization. This effect is likely the result of a reduction in retinal and lens size of PTU-treated eyes and is not related to melanization inhibition. This is because the eye size of tyr, a genetic mutant of tyrosinase whose activity is inhibited in PTU treatment, was not reduced. As PTU contains a thiocarbamide group, which is presented in many goitrogens, suppressing thyroid hormone production is a possible mechanism by which PTU treatment may reduce eye size. Despite the fact that thyroxine level was found to be reduced in PTU-treated larvae, thyroid hormone supplements did not rescue the eye size reduction. Instead, treating embryos with six goitrogens, including inhibitors of thyroid peroxidase (TPO) and sodium-iodide symporter (NIS), suggested an alternative possibility. Specifically, three TPO inhibitors, including those that do not possess thiocarbamide, specifically reduced eye size; whereas none of the NIS inhibitors could elicit this effect. These observations indicate that TPO inhibition rather than a general suppression of thyroid hormone synthesis is likely the underlying cause of PTU-induced eye size reduction. Furthermore, the tissue-specific effect of PTU treatment might be mediated by an eye-specific TPO expression. Compared with treatment with other tyrosinase inhibitors or bleaching to remove melanization, PTU treatment remains the most effective approach. Thus, one should use caution when interpreting results that are obtained from PTU-treated embryos.