New axolotl study gives researchers a leg up in work towards limb regeneration

Researchers supported by the U.S. National Science Foundation have discovered that it is not how much of a key molecule that allows axolotls to regenerate limbs properly, it is how little. This new knowledge moves researchers closer to enabling tissue repair and, possibly, limb regeneration in humans.

"Axolotls are a species of salamander that have the ability to regrow limbs and repair organ tissue," said Anna Allen, a program officer in the NSF Directorate for Biological Sciences. "Based on previous work, researchers knew that a particular molecule told cells to start the process of regrowth but how cells knew where they were along a limb and, therefore, what structure to build in that location remained a mystery."

The new work, led by James Monaghan, a professor of biology and director of the Institute for Chemical Imaging of Living Systems at Northeastern University, shows that the key is how that critical molecule, retinoic acid, degrades. An enzyme whose only job is to destroy retinoic acid is extremely prevalent at the far end of the limb (the wrist) but much less prevalent at the shoulder, meaning the reverse for retinoic acid. It is this decreasing amount of retinoic acid that allows the cells to know if they are at the shoulder, mid-limb, or wrist.

Building on their findings, the researchers used CRISPR technology to turn off certain genes to help identify which genes were involved in various aspects of limb regeneration. They found one gene, Shox, which has a role in human height, was critical in directing the shaping of parts of a limb near the shoulder. Other genes are important in shaping further out portions. When these genes were deactivated, limbs still regenerated but not to the proper length. Because axolotls and humans share these same genes and it is only whether or not they can be accessed at the right time, this information provides a genetic and molecular instruction manual that moves scientists closer to enabling tissue repair — and, maybe, limb regeneration — in humans.

"We are still a long way from humans regrowing limbs," added Allen. "But, while that may still be science fiction, we are now one step closer to repairing lost or damaged tissue rather than just having it scar over."

NSF has funded other work looking at the regenerative properties of axolotls, including to understand the function of genes involved in regeneration in the species and fish that can regrow their fins and how cells convert stimuli into electrochemical activity during regeneration.