Researchers Identify Key Pathway in the Pupil’s Response to Light

Investigators at Washington University School of Medicine in St. Louis have demonstrated that a particular protein is important for the eye’s pupil to respond to light. The discovery may help scientists learn more about the eye’s role in non-visual functions such as the synchronization of the body’s internal, circadian clock.

The team was led by Russell N. Van Gelder, M.D., Ph.D., assistant professor of ophthalmology and visual sciences and of molecular biology and pharmacology. Reporting in the Jan. 10 issue of the journal Science, the researchers say that mice that lack the two main types of photoreceptor cells in the retina ? rods and cones ? as well as proteins in the retina called cryptochromes, lose about 99 percent of their sensitivity to light.

“In the past, it was assumed that the eye functioned pretty much like an old-style camera,” says Van Gelder.

He says scientists believed that rods and cones in the retina are similar to film in a camera. Light enters through the cornea, is focused by the lens, and an image forms on the retina. Rods and cones then convert light into electrical signals that can be carried by the optic nerve into the brain, where the “film” could be “developed.”

“But that interpretation can’t account for the fact that the pupils of mammals with no functional rods and cones still open wider in dim light and get smaller in bright light,” Van Gelder explains. “How would the pupil know it was supposed to open and close if there weren’t any working photoreceptors to detect light in the retina?”

Part of the answer is that there still are cells that detect light in the retina of these blind mice, even in the absence of rods and cones. A study published in Science last February demonstrated that a subset of inner retinal cells, or ganglion cells, also respond to light.

That discovery kicked off a search for the proteins, or photopigments, that ganglion cells might use to translate light into nerve impulses. Rods and cones use vitamin-A-based proteins called opsins. But in this study, Van Gelder and colleagues examined vitamin-B-based pigments called cryptochromes.

“We know from genetic studies that the plant, Arabidopsis, and the fruit fly, Drosophila, use cryptochromes as photopigments, but it has been difficult to demonstrate that cryptochromes might be important in the mammalian eye,” Van Gelder says.

He and his colleagues tested the pupil’s response to light in four types of mice: normal mice, mice lacking cryptochromes, mice without rods and cones, and mice without cryptochromes, rods and cones. As has been shown previously, it took about 10 times more light to make the pupil constrict in mice lacking rods and cones. But mice that also lacked cryptochromes needed more than 100 times as much light as normal mice to make the pupil constrict. The results imply that without cryptochromes the ganglion cells in the retina were unable to sense or communicate differences in light.

“This suggests that the eye really isn’t like an old-style camera,” Van Gelder says. “As in a modern camera, there also appears to be a light meter, which involves ganglion cells that seem to rely on cryptochromes.”

In a related paper in the same issue of Science, a group led by King-Wai Yau, Ph.D., at the Johns Hopkins University, has shown that mice lacking another potential photopigment called melanopsin also have abnormal pupillary responses.

“Together these studies suggest a rich and complex non-visual photoreceptive system in the inner retina,” Van Gelder says.

He says this light meter-like system seems to be important in a different brain pathway than the normal visual pathway. The light-sensitive ganglion cells connect to areas of the brain involved in unconscious activities. Their major connection is to a part of the brain called the suprachiasmatic nucleus, which is where the body’s internal circadian clock is located. As a result, Van Gelder believes these cells play an important role in synchronizing the internal clock to external light cycles, and probably are essential to tasks such as recovery from jet lag or adapting to working the late shift.

“This study doesn’t definitively demonstrate that cryptochromes are the key photopigment that ganglion cells use, but we think it does demonstrate that they are part of an important pathway through which the eye tells the brain whether it’s light out, what season it is, and so on, even in the absence of vision,” Van Gelder says. “Cryptochrome genes are found in many other forms of life, including plants. They help tell plants what season it is and when to flower, and we believe these same kinds of genes also may be working in mammalian eyes to help modulate important, non-visual light detection tasks.”

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Van Gelder RN, Wee R, Lee JA, Tu DC. Reduced pupillary light responses in mice lacking cryptochromes. Science, p. 222, Jan. 10, 2003.

This research was funded by grants from Research to Prevent Blindness, the Association of University Professors of Ophthalmology and the National Eye Institute.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.