The anatomical and functional restoration of parts removed from an organism is known as regeneration. In the regenerating amphibian limb and in tissue regeneration in certain sensory organs, this process occurs under the influence of nerves. In other systems, such as liver regeneration and most instances of tissue repair, nerves are not required. One determinant of whether nerves are required for regenerative growth may be the degree of vascularization in the injured, responding tissue or organ. The early, nerve-dependent blastema of the regenerating limb is almost completely avascular except in its overlying skin. The molecular basis of the nerves’ growth-promoting effect is not known. Of the candidate molecules proposed, the nutritive factor transferrin, which is also released from capillaries, fits most closely to what is known of the neural effect in limb regeneration. Other candidates proposed as mediators of this activity include Fibroblast growth factors (FGFs), neuregulins and anterior gradient protein (nAG).

Key Concepts:

• Amphibian limb regeneration and other examples of epimorphic (blastema-based) regeneration usually depend on trophic factors provided by peripheral nerves.
  
• All nerve types can supply the growth requirement, which appears to be a nutritive factor that sustains cell cycling rather than a mitogenic signal to trigger cell cycling in dedifferentiating limb cells.
  
• Other nerve-dependent regenerating systems, such as regeneration of taste buds and corneal repair, lack a direct, extensive vasculature.
  
• Regenerating systems not requiring nerves, such as liver regeneration and seasonal regrowth of antlers, are not epimorphic and the regenerative process does not involve a blastema.
  
• Candidate factors for the neural effect include neuregulins, the newt anterior-gradient protein (nAG), and the plasma-derived trophic factor transferrin.
  
• Transferin is transported and released axonally and is required for cell cycle progression in a manner consistent with the effects of denervation on limb blastema cell proliferation.