Limb regeneration guide for axolotls

A recent paper by Otsuki and colleagues investigates the molecular mechanisms driving limb regeneration in axolotl

The question

You may know the axolotl (Ambystoma mexicanum), its funny face and gills floating around its head.

What you may not know is that it is also a model organism for organ regeneration thanks to its ability to regenerate many body parts, including its limbs. This is possible because cells know and remember where they are and can use this knowledge to inform the regeneration process. Cells found at the front of the limb possess so-called anterior identity, while those at the back hold posterior identity information. After amputation, cells from the anterior and posterior parts of the stub meet and trigger correct limb regeneration.

But how do cells know to produce a new limb after limb amputation, and not a tail or head instead?

The molecular bit

A recent study by Otsuki and colleagues¹, highlighted in a News & Views article², investigates the process of limb regeneration in axolotl through transgenic lines, transcriptomics and grafting experiments.

Otsuki and colleagues found that posterior identity in axolotl is established and maintained by a positive feedback loop that involves Hand2, a protein that controls the expression of other genes, and Shh (Sonic hedgehog), a signalling protein involved in limb growth. During development, Hand2 is expressed in posterior cells, and it is present at a steady state in adults. During regeneration, Hand2 is necessary and sufficient to induce the expression of Shh, which in turn activates Hand2 expression in nearby cells, sustaining the establishment of posterior identity in the new limb. After regeneration, Shh expression stops but residual Hand2 ensures lasting positional memory.

The unexpected discovery and why it matters

Interestingly, Otsuki and colleagues were able to rewire anterior-posterior memory, but only during regeneration and in one direction: anterior cells can stably acquire posterior identity when placed in posterior zones (or upon transient Shh signalling), but the opposite leads to defective limb regeneration.

The results presented by Otsuki and colleagues represent an important step forward in the understanding and manipulation of organ regeneration, and future studies into therapeutic applications in humans will benefit from this important work.

References

1. Otsuki, L., Plattner, S. A., Taniguchi-Sugiura, Y., Falcon, F. & Tanaka, E. M. Molecular basis of positional memory in limb regeneration. Nature 1–9 (2025) doi:10.1038/s41586-025-09036-5.

2. Wu, S. Y. C. & Whited, J. L. How axolotl cells ‘remember’ development to rebuild a lost limb. Nature d41586-025-01447–8 (2025) doi:10.1038/d41586-025-01447-8.

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