Clue to the mystery of limb regeneration revealed

A tiny creature with gills, a smile, and bright green skin has just given scientists a key clue to solving one of biology's greatest mysteries: limb regeneration.

Aquatic salamanders called axolotls are known for their unusual ability to regenerate limbs lost through injury or amputation. Now, researchers have learned more about the complex process behind this superpower in a new study published in Nature Communications.

"A long-standing question in the field has been what signals tell cells at the injury site to regenerate just the hand, for example, or to regenerate an entire arm," said study senior author James Monaghan, a professor of biology and director of the Institute for Chemical Imaging of Living Systems at Northeastern University.

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It turns out that a substance called retinoic acid, commonly found in retinol acne treatments, is responsible for signaling which parts of the body need to regenerate.

Retinoic acid is also important in the development of human embryos, as it tells cells where to develop heads, legs, and feet, Monaghan explained. However, for an unknown reason, most of our cells lose the ability to "hear" the molecule's regenerative signals during pregnancy.

And while regenerating entire human limbs still seems like science fiction, Monaghan said that studying the signaling function of retinoic acid in these amphibians could help develop new methods of human healing and gene therapies.

Axolotls don't naturally glow in the dark. To observe retinoic acid signaling, Monaghan's team used genetically modified axolotls that emit a fluorescent green glow where the molecule activates injured cells.

Initially, the research team took a more "Frankensteinian" approach by injecting excessive amounts of retinoic acid into the salamanders' systems and observing the effect. At the amputation site, the axolotls grew larger than necessary, replacing one hand with a full arm.

"If you inject a lot of retinoic acid into (a lesion), you turn on all these genes that probably have nothing to do with the patterning that's required," explained Catherine McCusker, an associate professor of biology at the University of Massachusetts Boston, who was not involved in the study but also researches salamander limb regeneration.

To better understand how axolotls used their natural levels of retinoic acid for limb regeneration, Monaghan and his team modified their approach.

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"We discovered that a single enzyme is responsible for breaking down retinoic acid in the axolotls' bodies," Monaghan explained, as quoted by CNN. When her team blocked this enzyme, the same Frankenstein effects were repeated. "This is really exciting and astounded us, because it shows that the levels of (natural) retinoic acid are controlled by its degradation."

In other words, an injured axolotl hand knows not to grow into an arm, in part because the enzyme CYP26B1 prevents the regeneration process from moving forward, McCusker explained.

So far, understanding this relationship in an axolotl's regenerative system is only one piece of the puzzle , Monaghan said.

The next step will be to identify exactly which genes retinoic acid targets within cells during regeneration to better understand the "pattern" those cells follow.