When an axolotl loses a limb, this is no cause to panic. It simply regrows a new one.
Muscle, bone, nerves, skin — rebuilt from scratch, perfectly arranged, toe by toe, joint by joint. Over the course of weeks, a fully formed limb emerges, indistinguishable from the original. To the salamander, this act of regeneration is routine. To us, it’s a biological miracle.
Scientists have marveled at this feat since Aristotle first described a lizard regrowing its tail thousands of years ago. But the deeper question has always been: how does the body know what to grow, and where? Which signals tell cells to make an elbow here, a wrist there, and five tiny toes at the end?
That ancient mystery now has a modern update. In a new study, a team of researchers at Northeastern University has traced this regenerative map to a molecule familiar to anyone who’s ever used anti-acne cream: retinoic acid. This chemical, a derivative of vitamin A, seems to act as a sort of internal GPS, telling cells where they are and what structure is missing.
What’s remarkable is not just the precision of this system, but its simplicity. Much of the hard work of regrowth — sculpting tissue into fully formed limbs — might boil down to tweaking the levels of a single molecule and the gene that controls it.
In other words, regeneration isn’t magic. It hinges on memory. Molecular memory. And the salamander’s cells remember very well.
The Molecular Compass of Regeneration
Retinoic acid was previously well-known for its role in embryonic development. It’s also the active ingredient in the acne drug Accutane, among many other skin care products.
In axolotls, retinoic acid acts like a molecular GPS. Its concentration changes along the length of a regenerating limb, helping cells determine their location and what structures they need to build. Higher levels of the molecule signal a more “shoulder-like” position; lower levels point toward the fingers.
But this gradient doesn’t happen on its own. A protein called CYP26B1 is vital for breaking down retinoic acid. Where this enzyme is more active, retinoic acid levels drop, creating a biochemical map of the limb.
When Monaghan’s team suppressed CYP26B1, they observed something astonishing. The regenerating limb lost its positional sense and began forming duplicate, misplaced segments — essentially, extra bones growing where they shouldn’t.
At a molecular level, this disruption triggered abnormal expression in genes involved in limb formation, including Meis1 and Shox, two homeobox genes already known to shape skeletal development.
In one experiment, the researchers deleted the Shox gene using CRISPR. The animals still regenerated their limbs, but the limbs were stunted, with shortened upper arms and forearms. The hands, however, developed normally. This shows that Shox is meant for forming the stylopod (upper limb) and zeugopod (forearm), but not the digits.
Interestingly, humans with mutations in SHOX can develop short stature and malformed limbs — a rare but real medical condition. The fact that axolotls use this gene in similar ways is a tantalizing sign that our own bodies may retain ancient, latent blueprints for limb regrowth.
Could We Regrow Limbs Too?
Monaghan is cautiously optimistic.
“It could help with scar-free wound healing but also something even more ambitious, like growing back an entire finger,” Monaghan says. “It’s not out of the realm [of possibility] to think that something larger could grow back like a hand.”
Retinoic acid is already present in the human body. Our fibroblasts — connective tissue cells — use it during development. But in adults, when we lose a limb, those cells build scar tissue instead of new bones and muscles.
What sets axolotls apart is not that they have a special gene humans lack. Instead, it’s that their cells “listen” to signals like retinoic acid and respond by switching on a developmental program, as if the limb were being formed from scratch.
“The cells can interpret this cue to say, ‘I’m at the elbow, and then I’m going to grow back the hand’ or ‘I’m at the shoulder. I have high levels of retinoic acid, so I’m going to then enable those cells to grow back the entire limb,'” Monaghan says.
This idea of reawakening embryonic programs in adult cells to regrow lost limbs may not be so “impossible” as previously believed. The study shows that even modest shifts in the body’s signaling chemistry can dramatically reshape tissues.
The Next Frontiers
The road to human limb regeneration is long. But every step — understanding the chemical gradients, the role of key genes like Meis1 and Shox, and the enzymes that regulate them — is building the foundation.
Other labs are joining the chase. McCusker’s own team recently mapped out how limbs figure out which side is up or down — a separate challenge in regeneration. And an Austrian team recently identified feedback loops that give axolotl cells a kind of “memory” of what used to be there.
Still, Monaghan’s study stands out for showing that just tweaking one enzyme can reprogram an entire limb’s identity.
But there are still questions. Why exactly do salamanders retain this regenerative power while humans don’t? Can we make our own cells pay attention to these ancient molecular cues again?
“If we can find ways of making our fibroblasts listen to these regenerative cues, then they’ll do the rest,” said Monaghan.
The findings appeared in the journal Nature Communications.
