The 'eyes' have it: Biologist studies fish for optic nerve solutions in humans

When our optic nerve is damaged – by glaucoma or diabetic neuropathy, for example – it’s basically game-over for our eyesight. The nerve can’t be healed and our vision loss can’t be restored.

But that’s not the case with fish, which can regenerate their optic nerve in 12 days and regain their eyesight after an additional 80 days after an injury.

UWM biologist Ava Udvadia just figured out how they do it, and she hopes that discovery will lead to treatment for eye ailments in humans.

Of injured eyes and growing cells

A nerve cell, or neuron, consists of three major parts: A body, Ava Udvadia which contains the nucleus of the cell; dendrites, which receive incoming information; and an axon, a “tail’ that connects the neuron to cells in another part of the body to transmit information. The optic nerve contains the axons of neurons that transmit visual information from the eye to the brain.

In the type of eye injuries Udvadia is studying, the initial injury is to the axons, while the cell bodies remain intact for a while. In order to repair the injury, the neurons need to regenerate their axons and reestablish connections with the brain.

That’s impossible for fully mature neurons in the central nervous system of mammals, which are locked into their current state. It’s not impossible for developing neurons, however, which got Udvadia thinking about how to reprogram damaged adult neurons.

Ava Udvadia

“Nobel prize-winning work on induced pluriopotent stem cells showed us that you can take a take a fully differentiated cell from an adult tissue and you could actually reprogram it – that is, back it up to a state where now, it could give rise to any type of cell in the body,” Udvadia said. “With a damaged optic nerve, we don’t want to back the neurons up that far. We want to keep them as neurons, but back them up to a state where they can rewire their connections to the brain. Fish can do it, mammals can’t. Why not?”

A good question, especially since fish and humans use similar programming to initially wire the visual system during development. That is, the same genes tell neurons to grow their extensions during development and to stop growing in adults. The difference between fish and humans is in the ability to turn the growth program back on after injury in adults.

The answer, Udvadia thinks, is in the arrangement of each species’ genetic information. This arrangement enables fish to “turn on” a genetic program that regenerates their nerve. The arrangement in mammals prevents the reactivation of the axon growth program.

A novel approach to experimenting

To understand how fish regenerate their optic nerves, Udvadia and her team took a different approach.

“In the past, people looked at regeneration as a single event. Our approach looked at it as actually being a series of events,” Udvadia said. “We know in development as the neuron is growing to make its connections – very specifically, the neurons in the eye making this connection to the brain – it has to go through a lot of different and complex environments.”

She and her team looked at several key points in the fish’s regeneration timeline:

This diagram shows the path an axon must travel to regenerate a damaged optic nerve in a fish. "DPI" indicates "Date Past Injury." Diagram courtesy of Ava Udvadia.

1. The injured neuron first has to grow past the site of the initial injury.

2. The neuron has to choose the correct crossroads when its connection reaches the juncture of the other optic nerve. It has to connect to the opposite hemisphere of the brain, rather than grow into the closest hemisphere or into the other eye.

3. The neuron has to reach the part of the brain responsible for processing visual images.

4. Finally, the neuron has to wire up correctly. If it doesn’t make the exact connections in the brain it’s supposed to, the fish won’t process images correctly, like pixels out of place on a computer screen.

At each time point, Udvadia asked two questions: What are the genes whose expressions are changing during each stage of regeneration, and what are the mechanisms regulating the changes at those time points?

A genetic map – for fish and mammals?

Udvadia found the genes whose expression was changing – some 7,000 of them. She and her team broke those down into categories of genes whose expression peaked early in the process, in the middle, and late in regeneration. That way, they could focus on groups of genes that peaked at the same time and understand what mechanism was responsible for regulating them.

They found not only sequences within the fish’s genetic information that could instruct the cell which genes to turn on and off for regeneration and when, but also changes in transcription factors – chemicals that bind to the DNA and control the genes for regeneration.

With the fish’s regeneration-associated gene programming identified and its regulatory sequences uncovered, Udvadia now faces a new task.

“If we can identify from among these transcription factors which ones are different in the response in mammals and fish, now we’re at a place to define what we need to tweak in mammals to get them to switch this program on,” Udvadia said.

Those are the next steps in her research. Udvadia hopes to begin working with mice to understand the genetic mechanisms at play when they receive such an eye injury. Eventually, she hopes that understanding how fish regenerate their optic nerves will open avenues for treating eye injuries in mammals and humans. Her research could even have implications for other nerve injuries in areas like the spinal cord.

Udvaida’s research was published in early October in "Scientific Reports," and she presented her work at the Society for Neuroscience’s conference in Chicago in mid- October.

By Sarah Vickery, College of Letters & Science