Table 1.

A brief description of the evidence for various candidate factors which have been suggested as essential nerve-derived mitogens during limb regeneration.

Factor	Relevant findings
Substance P	Increase in substance P-liked immunoreactivity in peripheral nerves after amputation.50 Immunohistochemically found in the blastema and reduced after denervation; has a mitogenic effect on cultured blastema cells which can be blocked by adding substance P antiserum to nerve co-cultures.49
Insulin	A blastema does not form if the limb is amputated following pancreatectomy.53 Insulin increases DNA and protein synthesis of blastemal cells in vitro; long-term exposure to insulin decreases the amount of time spent in G1.52 For review see.51
Transferrin	Immunohistochemically found in both Schwann cells and axons; expression increases in nerves during limb regeneration and is decreased upon denervation; appears to be secreted by the ends of nerves after axotomy.54 Blocking transferrin with antiserum blocks the growth-promoting effects of nerve extracts on cultured blastemal cells; treatment with transferrin maintained DNA synthesis in denervated blastemas in vivo.55
Nerve growth factor	Injections increased the length of the regenerate and the speed of digit formation.56 Treatment with NGF increases the labeling index of dorsal root ganglia, as does amputation of the limb, although the effects are not combinatory.57
Newt anterior gradient	Expressed in the blastema and lost upon denervation; stimulates blastemal cell proliferation in culture; electroporation into denervated newt limbs rescues regeneration.62 Stimulation of blastemal cells can be blocked with a mutation to the anterior gradient active site or the addition of antibody to the receptor Prod1.93
Fibroblast growth factors and BMPs	Stimulates the proliferation of cultured blastemal cells in a dose-dependent manner.58 Upregulated during regeneration and downregulated after denervation.59 Injection into denervated blastemas shows dose-dependent stimulation of blastemal cell mitotic index.60 Supplementation with FGFs and Gdf5 induces nerve-independent accessory limb formation.61 FGF8 and Bmp7 electroporated into dorsal root ganglia are expressed at the ends of peripheral nerves; knockdown of Fgf8 and Bmp7 blocks blastema formation72
Neuregulin-1	Present in the newt nervous system and the regenerating blastema; lost upon denervation; increases proliferation in cultured blastemal cells.80 Expressed in the dorsal root ganglia and peripheral nerves of newts; injections into denervated newt blastemas induced regenerative growth.81 Found along with its active receptor ErbB2 in the regenerative blastema and lost upon denervation; supplementation rescues regeneration to digits in denervated limbs; inhibition of ErbB2 signaling blocks regeneration.78
Oncostatin M and PDGF-AA	Expressed in the regenerating mouse digit tip; supplementation rescues regeneration after denervation.12