September 2009




Zebra fish helping to understand human blindness

by Maxine Lipner Senior EyeWorld Contributing Editor


New gene mutation detected

A gene mutation of the tbx2b gene recently identified in zebra fish may hold the key to understanding the development of a form of human blindness known as enhanced S-cone syndrome, according to Ann C. Morris, Ph.D., Florida State University, Tallahassee, Fla. In the study published in the February 10, 2009, issue of the Proceedings of the National Academy of Science, investigators led by Karen Alvarez-Delphin, Department of Biological Science and Program in Neuroscience, Florida State University, in conjunction with James M. Fadool, Ph.D., associate professor, Florida State University, zeroed in on a mutation that results in excessive formation of rods in zebra fish.

Such zebra fish provide a welcome addition to the ophthalmic genetic testing arsenal for a variety of reasons. “Zebra fish are vertebrates like humans, and all vertebrates have very well conserved architecture to the retinas,” Dr. Morris said. “The zebra fish retinas are organized in the same way as human retinas.” One of the advantages to using zebra fish over other vertebrates is that they develop externally rather than in-utero like mammalian animals. “We are able to access the animal from the first stage of development,” Dr. Morris said. “Also, the developing zebra fish embryos are completely transparent so we can study the development of an eye in a live animal by light microscopy or by other imaging methods in a much easier way than is possible to do with mammalian model systems.”

New mutation found

In the recent study, investigators found a mutation in the tbx2b gene. “The tbx2b gene encodes a protein which is a transcription factor,” Dr. Morris said. “This protein works to turn on or off other genes.” Tbx2b had been identified previously in other developmental systems. “It was known to be involved in the development of the heart, but it was not identified as having a role in the development of retinal photoreceptors,” Dr. Morris said.

When investigators used immuno-labeling to mark all of the developing rod photoreceptors, which mediate dim light vision, they discovered something unexpected. “Karen [Alvarez-Delphin] saw that there were far more rod photoreceptors than you would expect to see in a normal larva at that age,” Dr. Morris said. “Not only were there too many rods, but there were also too few UV cones.”

This was surprising since fish tend to have very good color vision. “Fish have four different kinds of cones that are sensitive to red, green, blue, and also UV light,” Dr. Morris said. “The UV cones were missing in these mutant animals.” This phenotype is the exact opposite of that found in a human retinal degenerative disease known as enhanced S-cone syndrome. “With enhanced S-cone syndrome, patients have more than the expected short wavelength sensitive cones and their rod photoreceptors degenerate.”

Investigators believe that there is likely a connection here. “In our fish we were seeing that they had too many rods and too few short wavelength sensitive cones,” Dr. Morris said. “So it seems as if there is some kind of link between making sure that the retina can make the proper number of UV or shortwave length sensitive cones and the proper number of rods, and that the transcription factor made by the tbx2b gene is involved in somehow regulating that.”

The use of zebra fish allowed for studying this in a way that is not possible in other models. “The tbx2b had not previously been picked up as being important in this process in mice and humans,” Dr. Morris said. “That is probably because if you have a mutation in this gene in a mouse it causes embryonic lethality because it is required for heart development.” As a result, mice with the damaged gene never make it far enough to see what happens with the retina.

Considering gene therapy

While there are currently no cures for retinal degenerative diseases such as enhanced S-cone syndrome, Dr. Morris sees the discovery as offering new hope. “There are so many different genes that when mutated result in RP [retinitis pigmentosa] or retinal degeneration, and there’s no current treatment that can restore the vision of people whose photoreceptors degenerate,” she said. “But there’s a lot of interest in gene therapy approaches.” If tbx2b does turn out to be an important switch for humans, too, it would potentially enable such gene therapy to be tried. “Knowing that tbx2b may play a role in rod photoreceptor and short cone photoreceptor development creates a possibility that could open the door to therapeutic interventions,” Dr. Morris said. This will require those who do human trials to pick up the mantle.

Going forward, investigators hope to take a closer look at the regulation process. “We know that tbx2b regulates switching genes on and off; somehow it’s through that process that it’s affecting the cell fate choices of the photoreceptors,” Dr. Morris said. “The next step is going to be trying to understand what genes tbx2b is turning on and off that are causing those decisions to be made.”

Editors’ note: Dr. Morris has no financial interests related to her comments.

Contact information

Morris: 850-645-8569,

Zebra fish helping to understand human blindness Zebra fish helping to understand human blindness
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