UT Southwestern Medical Center researchers have identified a gene called Lipe that appears to be pivotal to retinal health, with mutations spurring immune activation and retinal degeneration. This is important because the retina is responsible for detecting the light that is transformed into vision. The findings, published in Communications Biology, provide clues about the mechanisms behind a variety of disorders affecting the retina, including macular degeneration and diabetic retinopathy.
Many retinal diseases are associated with activation of immune cells in the retina. We're showing that Lipe could play an important role in controlling this process."
Rafael Ufret-Vincenty, M.D., Study Leader, Associate Professor of Ophthalmology at UTSW
Dr. Ufret-Vincenty explained that his lab has long been interested in identifying genes essential to retinal health. To accomplish that goal, these researchers teamed up with the lab of Bruce Beutler, M.D., Professor of Immunology and Internal Medicine and Director of the Center for the Genetics of Host Defense at UTSW. Dr. Beutler received the 2011 Nobel Prize in Physiology or Medicine for his discoveries involving the activation of innate immunity.
Much of Dr. Beutler's work has taken advantage of an approach called forward genetics, in which a chemical is used to induce random mutations in the genes of mice. By identifying how these mutant animals differ from animals that don't carry the mutations and then studying their genomes, researchers can identify the genes responsible for various effects.
Using forward genetics, Dr. Beutler and his colleagues generated nearly 6,000 mutant mice, which Dr. Ufret-Vincenty's team screened for markers of immune activation in the retina. Eventually, they identified several genes including Lipe that, when mutated, caused these animals to develop spots visible in the fundus, or the back of the eye. Further investigation showed these spots were activated immune cells known as microglia that collected underneath the retina.
Narrowing their focus to Lipe, which plays a role in lipid metabolism, the researchers used a genetic technique to turn off its function in another group of mice. Their results showed that mice without a functioning Lipe gene also had fundus spots, confirming that this gene plays an unexpected role in regulating immune activity in the retina. Further investigation showed that when Lipe was inactivated, the outer layers of the retina degenerated, causing vision loss in these animals over time.
Dr. Ufret-Vincenty said it's unclear why the loss of Lipe function led to an immune reaction and, ultimately, vision loss in these animal models. Additional experiments showed that the balance of lipids in the eyes of the affected mice differed significantly from wild type mice, a clue the researchers plan to investigate in future research. The researchers also plan to study whether Lipe plays a role in retinal degeneration in mouse models of diabetes.
Other UTSW researchers from the Department of Ophthalmology who contributed to this study were first author Seher Yuksel, Ph.D., Postdoctoral Researcher; Bogale Aredo, Ph.D., Senior Research Scientist; Yeshumenesh Zegeye, B.S., Research Assistant; John D. Hulleman, Ph.D., Assistant Professor; and Igor A. Butovich, Ph.D., Associate Professor. Additional collaborators were Laurent Gautron, Ph.D., Assistant Professor, Internal Medicine; and Center for the Genetics of Host Defense members Miao Tang, M.D., Instructor, Xiaohong Li, M.D., Ph.D., Assistant Professor, Sara Ludwig, Ph.D., Assistant Professor, and Eva Marie Moresco, Ph.D., Assistant Professor.
Dr. Beutler is a Regental Professor and holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.
This research was funded by grants from the National Eye Institute (1R01EY033181, R01EY027349), the National Eye Institute Center Core Grant for Vision Research (P30EY030413), the National Institutes of Health (R01AI125581, U19AI100627), the VanSickle Family Foundation, UT Southwestern Synergy Grant, and the David M. Crowley Foundation; and by the Josephine Long Biddle Chair in Age-Related Macular Degeneration Research, the Lillian and James Cain Endowment in Vision Loss, the Anne Marie and Thomas B. Walker Jr. Fund for Research on Macular Degeneration, and the Department of Ophthalmology at UTSW.
Yuksel, S., et al. (2023). Forward genetic screening using fundus spot scale identifies an essential role for Lipe in murine retinal homeostasis. Communications Biology. doi.org/10.1038/s42003-023-04870-7.