UB Study Finds Novel Clues to Retinal Degeneration Process

Their findings suggest a reason for the development of retinal disorders in later life and may lead to new avenues of research.

The research team found that activation of the transcription factor protein Onecut1 is essential for the formation of horizontal cells, says Xiuqian Mu, PhD, assistant professor of ophthalmology.

These neurons regulate and integrate input from the rods and cones (photoreceptors) that allow eyes to adjust to variations of light and send light-derived electrical impulses to the brain. Both rods and cones are needed for good vision.

In a related, but unexpected discovery, the researchers found that retinal horizontal cells “are required for maintaining the integrity of the retina and that their deficiency can lead to photoreceptor degradation,” says Mu.

“Because photoreceptor degradation is believed to be a major factor in diseases such as retinitis pigmentosa and Leber’s congenital amaurosis, this finding is novel and significant,” he notes.

The research team genetically engineered mice without Onecut1, resulting in a horizontal cell count 80 percent below normal.

Surprisingly, when these mice reached adulthood—at about 8 months—they had less than half the normal level of photoreceptor cells.

“When the formation of horizontal cells was blocked, the photoreceptors didn’t get what they needed, so they degenerated and died later on,” says study co-author Steven J. Fliesler, PhD, Meyer H. Riwchun Endowed Chair Professor and vice-chair and director of research in the Department of Ophthalmology, and research health scientist at the Buffalo VA Medical Center.

The death of these once-normal photoreceptor cells is “somehow driven by the deficiency in horizontal cells,” Mu concludes.

Previous research has focused on genes that directly affect photoreceptor cell development, explains Mu, so this secondary route to degeneration suggests new areas of study.

As one example, “important supportive interactions between horizontal cells and photoreceptors may be required to maintain photoreceptor function and viability,” Fliesler hypothesizes.

The study, “Onecut1 is Essential for Horizontal Cell Genesis and Retinal Integrity,” has been published in The Journal of Neuroscience.

UB contributors also include first author Fuguo Wu, a postdoctoral researcher; Renzhong Li, a former UB postdoctoral researcher; Tadeusz J. Kaczynski, a neuroscience doctoral student; and Darshan Sapkota, a biochemistry graduate student.

Other co-authors are from the State University of New York (SUNY) Upstate Medical University, the University of Medicine and Dentistry of New Jersey, the University of Oklahoma Health Sciences Center and Vanderbilt University Medical Center.

Funders include the Whitehall Foundation, the National Eye Institute, the SUNY Research Foundation Research Collaboration Fund, Research to Prevent Blindness, the Oklahoma Center for the Advancement of Science and Technology and the Lions of Central New York. Some resources and facilities were provided by the VA Western New York Healthcare System, part of the national Veterans Health Administration.