November 2001

From University of Michigan Health System

Clues to development of eye's light-sensitive cells found

Study has implications for understanding macular degeneration and retinitis pigmentosa

ANN ARBOR, MI - A paper published electronically this week by Nature Genetics offers important new insights into the development and differentiation of rod and cone photoreceptors, the light-sensitive cells in the eye's retina that initiate vision and are essential for clear sight.

A team led by Anand Swaroop, Ph.D., professor of ophthalmology and vision research scientist at the University of Michigan Health System's Kellogg Eye Center, has demonstrated that the retinal protein Nrl is required for rod development and, in fact, acts as a "molecular switch," signaling the cells to develop into rods rather than cones.

Working with Swaroop, research investigator Alan J. Mears, Ph.D., deleted the gene that makes Nrl in mice, creating an Nrl-knockout strain that developed a retina without rod photoreceptors.

"These findings are important because they will allow us to understand how rods are formed, and more importantly how we can save the cones," says Swaroop. "Currently, the cellular pathways and regulatory molecules that determine exactly how photoreceptors develop are poorly understood. If we learn more about this process, we may be able to pinpoint ways to intervene with gene or drug therapy to treat certain types of vision loss."

A better understanding of rods and cones may help researchers treat retinitis pigmentosa (RP) and macular degeneration, two major eye diseases that involve loss of photoreceptors, resulting in slow but progressive vision loss.

Swaroop explains that photoreceptors are post-mitotic cells; meaning that when they degenerate, they cannot be replaced and a person's vision suffers. Cone photoreceptors enable color vision and visual acuity in bright light. Rods, which dominate the retina, are responsible for night vision.

To date, most research has centered on rods, in part because they make up almost 95% of the photoreceptors in human retina. Much less is known about cones, including the important but puzzling question as to why they do not generally survive without rods in diseases like RP.

Swaroop believes that the Nrl knockout mouse - that is, the mouse bred to have only cone cells - can be used to investigate this behavior. Even though the mice do not have a well-defined macula (a region of the retina that is richer in cones than other parts of the retina), Kellogg researchers hope that this mouse model will allow them to identify the molecules needed for cone function and survival. This knowledge holds promise for developing treatments for macular degeneration, a disease in which photoreceptors in the macular area of the retina die off.

As part of the study, researchers also examined the effect of age on cone function in the absence of rods, recording electrical activity in the retina of Nrl knockout mice at different times after birth. The responses did not change significantly up to 31 weeks, suggesting that cones can survive without rod function. This finding has encouraged Swaroop and colleagues to continue to explore how to keep cones alive longer.

The Nrl gene was discovered by Swaroop's group in 1991 at the Kellogg Eye Center. Over the years, his laboratory has shown that Nrl is a key molecule, which controls the expression of rod-specific genes, including rhodopsin, the visual pigment contained in rods.

Recently, Prabodha K. Swain, Ph.D., a post-doctoral fellow at Kellogg, working with investigators at University of Pennsylvania and in France, showed that Nrl is present only in rods and not in cones. While these investigations were in progress, Mears started to develop the Nrl-knockout mouse to study the role of Nrl in a living animal.

During development, retinal stem cells differentiate into photoreceptors in response to external and internal cues. Since Nrl is needed for rods to develop, it will be important to know what cues turn Nrl on. In addition, because the precursor, or stem, cells that give rise to rods and cones experience delays before expressing a specific cell type, there must be some additional cues that signal rod differentiation. Swaroop explains that if scientists can understand these cues, they may eventually be able to guide the stem cells in the diseased retina of an adult eye to generate new rods.

"We have also started to use microarray technology (eye DNA chips) in an effort to compare cellular pathways for rod differentiation in normal and knockout mice," says Swaroop. "And as we learn more about the cone-only retina, we hope to find as yet undiscovered cone genes that can then be tested for mutations linked to macular degeneration and cone dystrophies."

Swaroop is Professor of Ophthalmology and Visual Sciences, and Associate Professor of Human Genetics at the University of Michigan Medical School. Part of the study was done in collaboration with Paul A. Sieving, M.D., Ph.D., previously Professor of Ophthalmology at Kellogg and now Director of the National Eye Institute.

The paper will appear at the Nature Genetics website, www.nature.com/ng/, on November 5, and in the December paper edition.












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