April 3, 2009

Purdue professor's insight leads to better understanding of vision loss

According to the National Eye Institute, blindness or low vision affects 3.3 million Americans age 40 and older, and retinal degenerative diseases, such as age-related macular degeneration and diabetic retinopathy, are some of the leading causes.

Yuk Fai Leung, an assistant professor of biological sciences, co-led a team that developed a new analysis method and identified key genes involved in retinal development. A paper detailing the work was published in the Proceedings of the National Academy of Sciences last fall.

"Once we know the genetic network that influences retinal development, we can begin to understand the changes in specific genes that lead to vision loss," Leung said. "With this information, treatments could be developed that would prevent or reverse the physical affects."

Leung also recently received a $25,000 award from Hope for Vision, a nonprofit foundation that raises money to develop treatments and cures for diseases that cause blindness.

Leung led the research with John E. Dowling of the Department of Molecular and Cellular Biology at Harvard University. The research team used the analysis method to identify genes that control cellular differentiation in the retina of zebrafish.

Zebrafish are closer to humans in eye development than mice or other animal models, Leung said.

The analysis method, called factorial microarray analysis, can examine thousands of genes at once and analyze several experimental changes at the same time. Examining several changes at once is critical for understanding how one change can lead to several others, Leung said.

"Some important changes could seem insignificant if examined in isolation," he said. "For example, both eating nutritious food and swimming for an hour are good for your health. However, if you eat right before swimming, you will probably get sick. Only by doing both at the same time is the issue identified."

Additional members of the research team and paper co-authors include Ping Ma from the Department of Statistics and Institute for Genomic Biology at the University of Illinois and Brian A. Link from the Department of Cell Biology, Neurobiology and Anatomy at the Medical College of Wisconsin.

The team compared the genetic makeup of normal fish with fish that were blind due to improper development of retinal cells. The cells begin on the same track as those in the normal fish but do not complete the final stage of development known as terminal differentiation.

Leung and his team were able to identify the genetic network that controls the terminal differentiation process and to examine the effects of different combinations of genetic changes at different stages within the developmental process.

"We still don't know a lot about eye development, so we need to gather knowledge to figure out what goes wrong in a disease situation," he said. "We know the genes involved, but don't know much about the downstream changes a mutation causes. This work sets up the framework and model that can be used to examine such cause-and-effect relationships."

Leung plans to study other developments to obtain a more complete picture of eye development.

This research was funded by the Croucher Foundation, Knights Templar Foundation, Merck Award for Genomics Research, National Eye Institute and National Science Foundation.

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

Source: Yuk Fai Leung, (765) 496-3153, yfleung@purdue.edu

Purdue News Service: (765) 494-2096; purduenews@purdue.edu

In a zebrafish recessive mutant young (yng), retinal cells are specified to distinct cell classes, but they fail to morphologically differentiate. A null mutation in a brahma-related gene 1 (brg1) is responsible for this phenotype. To identify retina-specific Brg1-regulated genes that control cellular differentiation, we conducted a factorial microarray analysis. Gene expression profiles were compared from wild-type and yng retinas and stage-matched whole embryos at 36 and 52 h postfertilization (hpf). From our analysis, three categories of genes were identified: (i) Brg1-regulaed retinal differentiation genes (731 probesets), (ii) retina-specific genes independent of Brg1 regulation (3,038 probesets), and (iii) Brg1-regulated genes outside the retina (107 probesets). Biological significance was confirmed by further analysis of components of the Cdk5 signaling pathway and Irx transcription factor family, representing genes identified in category 1. This study highlights the utility of factorial microarray analysis to efficiently identify relevant regulatory pathways influenced by both specific gene products and normal developmental events.

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