Nerve of newt: A soluble factor guiding neural regeneration in amphibian limb regrowth

The ability of salamanders to regenerate lost limbs has long fascinated biologists, and the prospect of stimulating such dramatic healing in humans attracts the attention of the translational research / regenerative medicine folks. A new study by Kumar et al. reveals a dramatic role for a factor not previously implicated in regeneration or wound healing:

The anterior gradient protein family member nAG is a secreted ligand for Prod 1 and a growth factor for cultured newt blastemal cells. nAG is sequentially expressed after amputation in the regenerating nerve and the wound epidermis-the key tissues of the stem cell niche-and its expression in both locations is abrogated by denervation. The local expression of nAG after electroporation is sufficient to rescue a denervated blastema and regenerate the distal structures. Our analysis brings together the positional identity of the blastema and the classical nerve dependence of limb regeneration.

This study is exciting for several reasons. Not only is nAG both necessary and sufficient to stimulate regeneration, but it is also a soluble factor. This makes it easier to envision a role for similar soluble factors in future medical regenerative applications. nAG isn’t a magical cure-all protein, but rather a very important factor secreted at a specific time during regeneration by the neural fibers as they regrow. The authors elegantly demonstrate that by adding nAG in the absence of re-innervation, somatic limb regeneration does occur, but without new nerve formation (as well as being deficient in skeletal muscle re-formation).

A human homolog of nAG has been identified, but has yet to be characterized.