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Human ARF Gene Blocks Zebrafish Regeneration

Usually it isn't worth noting that researchers have found a way to break a specific biological process; typically that is a very early stage in finding out how things work, pull out the pieces one by one and see what happens, taking place long before the emergence of a decent overall picture of the situation. Here, however, researchers have broken regeneration in a much more interesting way, a part of ongoing efforts to identify exactly why it is that zebrafish, like salamanders, can regrow entire limbs and organs while mammals cannot. The ultimate goal here is to find out whether the necessary machinery for adult organ regrowth exists at all in humans, a suppressed part of our evolutionary heritage, and if so, build a way to safely turn it on:

Insights from creatures like zebrafish and salamanders, which routinely regrow damaged tails, limbs, jaws and even hearts, may one day endow humans with heightened regenerative abilities. "In the last 10 to 15 years, as regenerative organisms like zebrafish have become genetically tractable to study in the lab, I became convinced that these animals might be able to teach us what is possible for human regeneration. Why can these vertebrates regenerate highly complex structures, while we can't?" Whether the regenerative powers of zebrafish and salamanders represent ancient abilities that mammals have lost, perhaps in exchange for advanced tumor-suppression systems remains an open question for biologists. Most tumor suppressor genes, being extremely useful for preventing cancer and for forming tissues during development, are broadly distributed and conserved across many different species. Recent studies, however, suggest that one, the ARF gene, arose more recently in the avian and mammalian lineage, and has no equivalent in the genomes of highly regenerative animals.

To explore whether this gene might play a role in preventing tissue regeneration in humans, the researchers added human ARF to the zebrafish genome and assessed how it affected the fishes' normal ability to regrow damaged fins after injury. They found that human ARF had no effect on the fishes' normal development or response to superficial injury, but when the researchers trimmed off the tip of a fish's tail fin, the gene became strongly activated and almost completely prevented fin regrowth by activating a conserved tumor-blocking pathway. "It's like the gene is mistaking the regenerating fin cells for aspiring cancer cells. And so it springs into action to block it. Humanizing a lower vertebrate species to study regeneration has not generally been used before, and to our surprise it turned out to be remarkably tractable. The gene fits right in very cleanly and completely alters the organism's response."

The discovery suggests that future efforts to promote regeneration in humans will likely require carefully balanced suppression of this anti-tumor system. The same pathway in humans theoretically could be blocked to enhance researchers' ability to grow model organs from stem cells in a laboratory dish, to enhance patients' recovery from injury. Since tumor suppressors are thought to play a role in aging by limiting the rejuvenating potential of stem cells, blocking this pathway could even be a part of future anti-aging therapies. However, any such interventions would come with significant risk of removing an important brake on the growth of tumors.

Link: https://www.ucsf.edu/news/2015/11/251746/human-gene-prevents-regeneration-zebrafish

Comments

Very interesting result. I hope an organ regeneration pathway is found in humans.

Posted by: Antonio at November 19th, 2015 11:07 AM

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