Understanding Inherited Blindness Through Zebrafish Eyes

Discovery of a gene in zebrafish that triggers congenital blindness could lead to new treatments for a similar disease in humans.

AsianScientist (Apr. 20, 2017) – In a study published in Scientific Reports, researchers report a zebrafish model of Leber congenital amaurosis (LCA), one of the most common causes of childhood blindness that accounts for five percent of all vision impairments.

LCA can be genetically transmitted to a child when both parents possess at least one dysfunctional copy of a gene involved in eye development. Although LCA is relatively common, the molecular mechanism behind the disease remains unclear.

Now, researchers in the Developmental Neurobiology Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) have found a similar syndrome in zebrafish. From this research, they aim to use zebrafish as a model to unravel the causes of LCA and therefore provide new leads for a treatment.

LCA affects the retina, the thin layer of tissue at the back of the eye that detects light as well as differentiates colors and communicates the information to the brain via the optic nerve. A healthy retina usually features light-sensitive cells—photoreceptors—called cones and rods. Cones are specialized in bright environment and detect colors while rods are used in dim light but are monochrome, which is why we see in black and white at night.

A person with LCA will display deformed or absent cones and rods. A total of 24 genes—including a gene called Aipl1—have been linked to LCA in humans and mice.

Using a genetically mutated zebrafish embryo that did not react to visual stimuli, the researchers discovered that zebrafish DNA contains two Aipl1 genes, namely Aipl1a and Aipl1b, which are active in rods and cones respectively.

The mutant—called gold rush (gosh)—presents a genetic mutation in the Aipl1b DNA sequence, and therefore losing Aipl1 activity in cone photoreceptors. Consequently, the cone photoreceptors showed a deformed morphology and sustained degeneration. Rods however were not affected, suggesting that the degeneration is cone-specific.

Probing further, the authors of the study also revealed that Aipl1 is critical for the stability of two enzymes—cGMP-phosphodiesterase 6 and guanylate cyclase—which mediate phototransduction, the process of converting light into an electrical signal. Without these enzymes, the zebrafish is unable to react to light stimulus as the information is stopped in photoreceptors and fails to initiate the transmission of visual information into the brain through the optic nerve.

The research indicates that Aipl1b gene is important for visual function and maintenance of cone photoreceptors in the zebrafish. Without it, cones do not detect light stimuli and degenerate during development.

“The gosh mutant is a good model for understanding the molecular and cellular mechanism of cone cell death and the pathological process of human LCA. Hopefully, this new knowledge will help to find a future cure for patients who suffer such a devastating disease as LCA,” said Dr. Maria Iribarne, first author of the study.

The article can be found at: Iribarne et al. (2017) Aipl1 is Rrequired for Cone Photoreceptor Function and Survival through the Stability of Pde6c and Gc3 in Zebrafish.


Source: Okinawa Institute of Science and Technology Graduate University; Photo: Shutterstock.
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