The Genetic GPS Behind Limb Regeneration: How Axolotls “Remember” How to Regrow Their Arms

Hand2 expression in axolotl limb, Otsuki et al. (2025). Creative Commons License.

In The Amazing Spider-Man, a brilliant but nefarious scientist, Dr. Curtis Connor, attempts to use genes from lizards to regrow his amputated arm. Ridiculous, right? Well, as it turns out, this sci-fi dream isn’t far off from what some regenerative medicine researchers are striving towards today.

In a recent study published in the journal Nature, scientists in the Tanaka lab at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences worked out some of the underlying principles of limb regeneration. These scientists used axolotls, which, just like the lizards Dr. Connor researched, can regenerate whole amputated limbs!

For axolotls, regenerating an arm is like an architect rebuilding a mansion after a fire. To reconstruct this complex building, an architect needs a blueprint. Without one, the architect could build a Chuck E. Cheese instead of a mansion. And without knowing how the rebuilt rooms need to fit onto the foundation, the architect doesn’t know how much needs to be rebuilt, or even what direction the house used to face.

Research has shown that cells in a regenerating axolotl arm also need a blueprint. In fact,

if cells don't know where they are, an axolotl might regenerate its arm flipped upside down, the wrong size, or accidentally make a tail instead.

Scientists have proposed that there are genes that control a cell's identity on different axes of the body. This is called “positional memory,” a coordinate system within the body that allows a cell to know its exact location, much like how latitude and longitude identify positions on a map.

Positional memory is very important for regeneration. Without it, regeneration won’t start at all. Once regeneration has begun, a cell's positional memory will determine what it divides into and what structures it becomes. In a regenerating arm, for instance, a cell with an on-the-surface identity would become skin instead of muscle. If that cell also had a far-from-shoulder identity, it might become the sensitive skin on your hand instead of the thick skin of your bicep. But how does a cell actually hold each of these identities?

Anterior-posterior identity in regeneration. Figure from Otsuki et al. (2025). Creative Commons License.

The Tanaka lab has answered this very question. In their 2025 paper, the researchers found a gene that may be responsible for a part of positional memory in the arm.

Scientists in the Tanaka lab specifically focused on the difference between anterior and posterior cells. On the arm, the anterior cells are on the thumb-side and posterior posterior cells are pinky-side.

This kind of positional memory is especially important for regeneration, since cells on the amputation stump have to recognize that they are from opposite ends for regeneration to start. When anterior and posterior cells meet in the middle of an injury, the formation of signalling centers to regrow the limb is initiated. If cells can’t recognize a difference between each other, regeneration will not happen.

To test what could be creating posterior versus anterior identity, researchers looked at all the genes active in these two locations. They found one big genetic difference between the two locations: a gene Hand2, was expressed in almost every posterior cell and none of the anterior.

Through a series of experiments, the researchers found that this gene, Hand2, is how cells know they are posterior, and that they need to form a signaling center after amputation.

Not only was this true, but it turned out that after the signaling center was formed, it could cause newly regenerated cells to express Hand2 and become posterior. This means that a regenerated arm also has positional memory, which is why axolotl limbs can regenerate multiple times!

The discovery of this incredible genetic circuit brings us closer to unlocking the potential of regenerative medicine and leads to even more exciting questions. Do humans also have positional memory, and do they maintain it in the same way? If so, would it be possible to trigger a dormant positional memory circuit? We might still be a ways away from regenerating a whole human arm, but these discoveries show it's all just a blueprint waiting to be decoded.

By Maya Hruskar

References

Otsuki, L., Plattner, S.A., Taniguchi-Sugiura, Y. et al. Molecular basis of positional memory in limb regeneration. Nature 642, 730–738 (2025). https://doi.org/10.1038/s41586-025-09036-5

Otsuki, L., & Tanaka, E. M. (2021). Positional Memory in Vertebrate Regeneration: A Century’s Insights from the Salamander Limb. Cold Spring Harbor Perspectives in Biology, a040899. https://doi.org/10.1101/cshperspect.a040899