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To Regrow Neurons, Fish Retinas Go Back in Time

Goldfish trapped in hourglass. Isolated on white background.

A squashed spider can regrow its leg; a pet lizard can easily regenerate a severed tail; earthworms grow new heads when cut in half. Unfortunately for us, though, somewhere along the evolutionary chain, humans, mice and other mammals lost the ability to regenerate damaged tissues. But what if we could get it back? In a new paper, neuroscientists from Johns Hopkins Medicine used insights from fish to regenerate eye cells in mice with vision damage.

“It’s a wonder of nature,” said Seth Blackshaw, a professor of neuroscience at Johns Hopkins Medicine. Zebrafish, a common model organism studied by biologists, have a remarkable ability to regenerate damaged tissue. Of particular interest to the Blackshaw lab, zebrafish can regenerate sensory neurons. These specialized nerve cells are responsible for receiving signals from the outside world. They help humans and other animals touch, taste, hear, smell and see. The back layer of the eyeball is called the retina, and it contains the sensory neurons needed to see. In response to damage, zebrafish can flawlessly regrow their retinal neurons up to 10 times. We can’t even do this once. “It seems really unfair,” said Blackshaw.

Blackshaw’s lab studies how to emulate this fish superpower in mammals, with the hope of eventually restoring the sight of people with vision loss.

“I think learning from species that are actually able to regenerate is the royal road to figuring out how to restore neurons lost in humans,” said Blackshaw.

In their recent publication in Science, the Blackshaw lab and collaborators examined how the zebrafish retina responds to damage, and compared it with what happens in mice, a species that, like us, has virtually no regenerative capabilities.

So how do zebrafish accomplish the miraculous feat of restoring lost retinal neurons? By turning back their developmental clock. To understand this, we first need to be introduced to glia, another cell type in the retina. Glia serve as helper cells to neurons. Both the neurons and the glia come from the same developmental ancestor, called a precursor cell. As zebrafish embryos develop, the precursor cell divides so that some of the resulting cells become neurons and some become the helper glial cells.

When fish retinal neurons are damaged by physical injury or infection, glial cells immediately go into an inflamed state, which sounds the alarm alerting the body that it needs to respond to the injury. Then, the glial cells start moving backward in developmental time. They become those ancestral precursor cells again, capable of developing into glia or neurons. Blackshaw calls this “development run in reverse.” The precursors then give rise to neurons to replace those that were damaged.

Why can’t mammals do that? Let’s take a look at what happened to the damaged neurons in the mouse retina. Although the retinal glia did their job and became inflamed to sound the alarm, Blackshaw’s group found repressor proteins that actively stopped the glia from going back in developmental time. Instead, they remained mature glia cells. But what if they could remove the barriers that prevented glia from becoming precursor cells again? When the researchers studied damaged mouse retinas that were genetically engineered to lack the repressive proteins, the glia responded to retinal neuron damage much like they did in zebrafish. They went back in time to become precursors, and then went “back to the future” as functional neurons.

Although their finding is an exciting step, there’s a lot that has to happen before researchers can try this method in people with vision loss. First, the newly regrown mouse neurons need to further develop the capacity to sense light. Without this, the retinal neurons aren’t useful for restoring lost vision. Second, researchers need to ensure that the regenerated neurons wire up with the rest of the brain circuitry. Even if scientists could make neurons that sense light, those signals need to be communicated to the rest of the brain for it to make sense of the message.

Blackshaw’s lab is currently working on both of these goals and is optimistic about future research. The group has already finished experiments that use a similar strategy to regenerate damaged neurons in the control center of the brain, the hypothalamus. These neurons wire up with existing circuits in the brain and respond normally to changes in body temperature or hunger, just as hypothalamus cells should. Blackshaw said these findings give him a lot of hope that his research will one day benefit not only those with vision loss, but also those suffering from neurodegeneration, multiple sclerosis and spinal cord injuries.

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