Retinal diseases are the leading cause of blindness in adults aged 60 and over, affecting millions of people worldwide. Pioneering research at the Levine Laboratory, Moran Eye Center, University of Utah is providing scientists with a new understanding of how the retina develops from conception to birth. This newest research is published in the July 24, 2013 issue of The Journal of Neuroscience.

Edward M. Levine, PhD, professor, ophthalmology and visual sciences, focuses his research on the study of retinal development in the embryo and neonate. The human eye begins to form within the first month of conception. At around 7 weeks, the retina begins to develop in the back of the eye 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 more than 70 distinct cell types that are grouped into seven major cell classes. One particularly hot topic in research today is how the seven different major retinal cell classes are generated in a successive yet overlapping sequence from just one common source of “multipotent retinal progenitor cells (RPCs)” and how the RPCs produce these 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 these properties. 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. Dr. Levine explains: “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." 

What the researchers discovered was that without the Lhx2 gene, the retina does not grow to its normal size and the RPCs produce too many of one cell class and too few of others. In one set of experiments, the researchers found that if Lhx2 was deleted at a particular stage, the RPCs became "stuck" and continued to overproduce one particular cell class, retinal ganglion cells, 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 classes 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 Dr. 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 to harness genes such as Lhx2 to efficiently produce specific retinal cell types for potential stem-cell based therapies.

Moran researchers partnered with scientists from the University 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, University of California, Irvine, California.

For more information please contact Moran Communications Manager Steve Brown at 801-587-7693 or visit the Moran Eye Center website at
Funded by grants from the US National Institutes of Health (NIH; RO1-EY013760,P30-EY014800) and by an unrestricted grant from Research to Prevent Blindness, Inc. to the Department of Ophthalmology and Visual Sciences, University of Utah.

Authors: 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.)