(SALT LAKE CITY)— Retinal diseases are the leading cause of blindness in adults aged 60 and over, affecting millions of people worldwide. Pioneering research published this week from the Levine Laboratory within the ÑÇÖÞ×ÔοÊÓƵ of Utah's John A. Moran Eye Center is providing scientists with a new understanding of how the retina develops from conception to birth.
Edward M. Levine, Ph.D., a professor of ophthalmology and visual sciences, has published new findings in July 24 edition of The Journal of Neuroscience. His research focuses on the study of retinal development in the embryonic stage. The human eye begins to form within the first month of conception. The retina begins to develop in the back of the eye at around 7 weeks and continues to develop into a complex network of nerve cells for several months until it is capable of converting the images that we see into electrical impulses. These impulses are sent to the brain, allowing us to enjoy the spectrum of colors and images that make up our visual world.
For well over a century, scientists have been studying how the retina develops, which in many ways, is similar to the formation of the most advanced parts of the brain. While the retina is a rather accessible part of the nervous system to study, its development is complex, involving seven major unique cell categories and more than 70 distinct cell types. One particularly hot topic in research today is how the seven different major retinal cell types are generated in a successive yet overlapping sequence from just one common source of "multipotent retinal progenitor cells (RPC)" and how the RPCs control the development of the seven cell categories of cells at the correct time and in their correct proportions.
The innovative research in this study demonstrates that the Lhx2 gene is a key regulator of retinal tissue growth and controls how many cells of each retinal cell type are produced. This important Lhx2 gene activates and helps manage the RPC as it builds the retina. Using state-of-the-art genetic techniques in mice, the researchers were able to "turn off" or inactivate the Lhx2 gene at multiple time points during retinal development.
"This approach allows us to wait until the first steps of eye development are completed. This is critical because if we simply turn off the Lhx2 gene from conception, eye development fails before a retina ever forms. By 'flipping a switch' to turn off Lhx2 at our discretion, we can allow the eye to pass through the initial stages of development and then test Lhx2's function when the retina is going through its growth and differentiation stages," says Levine.
What the researchers discovered was that without the Lhx2 gene, the retina does not grow to its normal size and the RPC produce too many of one cell type and too few of others. In one set of experiments, the researchers found that if Lhx2 was deleted at a particular stage, the RPC became "stuck" and continued to overproduce the one cell type well after their production normally ceases. But if they waited a day or two later to delete Lhx2, the production of a different set of cell types was altered.
"These findings tell us that Lhx2 not only controls how many retinal cells will be produced, but also for how long. And they reveal the stages when the retinal RPC shift into the next phase of cell production," says Levine. "This is exciting because we are starting to understand how the complex cellular diversity of the retina is achieved."
The next step is to decipher the molecular circuitry that Lhx2 uses to control retinal cell diversity, which will not only allow researchers to get closer to probing the mystery and beauty of how our nervous system forms, but will provide clues about how and when to turn off the Lhx2 gene to efficiently produce specific retinal cell types for potential stem-cell based therapies.
Moran researchers partnered with scientists from the ÑÇÖÞ×ÔοÊÓƵ of Utah's Department of Neurobiology and Anatomy, Interdepartmental Program in Neuroscience, and the Department of Human Genetics; and the Department of Pathology and Laboratory Medicine, ÑÇÖÞ×ÔοÊÓƵ of California, Irvine, California.
The research was funded by grants from the National Institutes of ÑÇÖÞ×ÔοÊÓƵ (NIH; RO1-EY013760,P30-EY014800) and by an unrestricted grant from Research to Prevent Blindness, Inc. to the ÑÇÖÞ×ÔοÊÓƵ of Utah's Department of Ophthalmology and Visual Sciences. Authors of the study include: Patrick J. Gordon, Sanghee Yun, Anna M. Clark, Edwin S. Monuki, L. Charles Murtaugh, and Edward M. Levine
P.J.G. was supported in part by an NIH Developmental Biology Grant.)
To view the complete study, visit: http://www.jneurosci.org.