Limb regeneration from amphibians to mammals.

The ability to regenerate complex appendages varies strikingly across vertebrates, yet the developmental principles that enable complete limb regeneration remain incompletely understood. In mammals, regenerative responses are largely restricted to distal digit tips, whereas amphibians - such as the axolotl - can regenerate entire limbs throughout adulthood. This contrast provides a powerful framework for dissecting how adult tissues rebuild form, pattern and proportion after injury. In this Review, we synthesize recent advances from mammalian digit tip regeneration models and amphibian limb regeneration to examine core challenges of regeneration, including the establishment of regeneration-permissive niches, endogenous reprogramming of adult cells into regeneration-competent progenitors, integration of positional information across limb axes, and regulation of growth and scale. We highlight how comparative and functional studies are revealing conserved developmental programs that support regeneration, as well as key constraints that limit their engagement in mammalian limbs. Rather than serving as a template to be replicated in mammals, the amphibian limb provides a blueprint for understanding whether and how developmental programs can be reactivated (or replaced) in adulthood and why they fail to be fully engaged in mammalian limb injuries.