Extreme Healing: Protein aids limb regrowth in newts

Chop off the leg of a salamander or newt, and the limb will slowly grow back. How the wounded stump regrows into a leg is poorly understood, but now researchers have identified a key protein behind this regenerative power.

Studying animals with such regenerative abilities might reveal ways to induce feats of radical self-healing in people, some scientists believe.

When a newt’s leg is severed, muscle cells at the site of injury revert to a less-specialized state, becoming stem cells. These stem cells then divide and grow to regenerate the limb.

Jeremy P. Brockes of University College London and his colleagues found that a protein called newt anterior gradient (nAG) is essential to the regeneration process. The researchers were trying to answer an intriguing question: If a newt’s leg is severed at the ankle, the stem cells will regrow a foot. When the leg is cut off at its base, however, identical stem cells will grow an entire leg. But how does the mound of stem cells know where it is?

“That’s a very profound question,” Brockes says. His team already knew that a compound in newts known as Prod 1 can provide a road map for cell regrowth. From the base of the animal’s leg to its foot, the concentration of Prod-1 slopes gradually from high to low. Searching for proteins that can bind to this marker compound, the scientists identified nAG, which is similar to a protein that helps guide brain development in vertebrates.

Although this finding alone didn’t tell the researchers how the stem cells would know where they are, they soon realized that nAG explains a different curiosity about limb regeneration. Newt embryos begin forming legs when the stubs have not yet developed nerves, but an adult newt’s leg will regrow only if the nerve running through it also regrows. If the nerve fails to grow for some reason, the stem cells at the wound won’t multiply. Scientists have been trying to explain why since the 1950s.

The nerve’s insulating sheath releases nAG, probably in response to chemical signals from the nerve, Brockes suggests. Even when the researchers blocked the nerve and sheath from regrowing, adding nAG to the stem cells was sufficient to cause the cells to resume dividing and to fully regenerate the limb, the researchers report in the Nov. 2 Science.

“Lo and behold, that’s all that you need to make the cells divide,” comments David Stocum, who studies limb regeneration at Indiana University–Purdue University Indianapolis. “That is truly impressive.”

Proteins similar to nAG exist in people and other mammals, but further research is needed to show whether mammalian cells have latent potential for such extreme regeneration.