Advances in Decoding Axolotl Limb Regeneration

Humans and other mammals are limited in their natural abilities to regenerate lost body parts. By contrast, many salamanders are highly regenerative and can spontaneously replace lost limbs even as adults. Because salamander limbs are anatomically similar to human limbs, knowing how they regenerate should provide important clues for regenerative medicine. Although interest in understanding the mechanics of this process has never wavered, until recently researchers have been vexed by seemingly impenetrable logistics of working with these creatures at a molecular level. Chief among the problems has been the very large size of salamander genomes, and not a single salamander genome has been fully sequenced to date. Recently the enormous gap in sequence information has been bridged by approaches that leverage mRNA as the starting point. Together with functional experimentation, these data are rapidly enabling researchers to finally uncover the molecular mechanisms underpinning the astonishing biological process of limb regeneration. The salamander experimental toolset has now largely caught up with the interest in understanding limb regeneration, finally allowing precise experimentation at a cellular and molecular level. A huge amount of transcript data has emerged from which to gather clues about how limb regeneration occurs. Differential gene expression analysis has enabled the identification of transcripts that are highly enriched, as well as highly repressed, in key tissues required for limb regeneration. These are prime starting points for hypothesis generation and functional experimentation. Several genes whose involvement would not have been predicted by candidate gene approaches have now been implicated in limb regeneration, underscoring the need to take unbiased approaches to gene discovery. De novo transcriptomes and reference-tissue sequence data are important new resources for the field.