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Regeneration: The Development of Rebuilding
As mentioned above, the regeneration of the salamander limb along the proximal-distal axis appears to follow rules similar to those that generate the developing limb. Indeed, the opposing retinoic acid-FGF gradients postulated for the development of the limb were first hypothesized for the regeneration of limb structures along this axis (Crawford and Stocum 1988). It is known that the size and pattern of the regenerated limb depend on the proximal-to-distal position of the amputation such that the limb generates only tissues that had been distal to the cut, replacing them in the appropriate pattern. What factors beyond retinoic acid and FGFs are controlling this pattern formation? Many different signaling molecules have been implicated, including the usual suspects: Wnts, BMPs, Hedgehogs, and Notch (reviewed in Satoh et al. 2015; Singh et al. 2015). But the story is not yet clear, and odd patterns of regeneration can result from applying some of these molecules. For example, if a regenerating salamander limb is exposed to retinoic acid, the blastema is reprogrammed to produce a full limb with all proximodistal structures, regardless of the position of the amputation (Maden 1983; Niazi et al. 1985; McCusker et al. 2014). Recent investigations of the signals related to the nerve’s role in regeneration induction have revealed new and old players. Recall from above that a denervated amputated limb will fail to regenerate. However, regeneration can be restored by implanting a bead coated with Neuregulin-1 regardless of the lack of nerves (see Figure 22.31C). In addition, if beads coated with BMP proteins or a combination of BMPs and FGFs are implanted in a wound site on a salamander limb, an accessory limb will form (Figure 22.32E; Makanae et al. 2014).
Developing Questions
The limb will regenerate only the distal tissues that were removed, which suggests that key positional information is resident in the salamander limb to provide instructions for cell fate patterning during regeneration. Treatment with retinoic acid, use of an epidermal graft from a contralateral position, or BMP and FGF signals can induce different types of growth where they normally would not occur, however. What are the key components of positional information? How is this positional information able to be maintained and accessed during regeneration?
Literature Cited
Crawford, K. and D. L. Stocum. 1988. Retinoic acid proximalizes level-specific properties responsible for intercalary regeneration in axolotl limbs. Development 104: 703–712.
PubMed Link
Maden, M. 1983. The effect of vitamin A on the regenerating axolotl limb. J. Embryol. Exp. Morph. 77: 273–95.
PubMed Link
Makanae, A., K. Mitogawa and A. Satoh. 2014. Co-operative BMP and FGF signaling inputs convert skin wound healing to limb formation in urodele amphibians. Dev. Biol. 396: 57–66.
PubMed Link
McCusker, C. D. and D. M. Gardiner. 2014. Understanding positional cues in salamander limb regeneration: implications for optimizing cell-based regenerative therapies. Disease Models Mech. 7: 593–599.
PubMed Link
McCusker, C., J. Lehrberg and D. Gardiner. 2014. Position-specific induction of ectopic limbs in non-regenerating blastemas on axolotl forelimbs. Regeneration 1: 27–34.
PubMed Link
Niazi, I. A., M. J. Pescitelli and D. L. Stocum. 1985. Stage-dependent effects of retinoic acid on regenerating urodele limbs. W. Roux’ Archiv f Entwicklungsmechanik. 194: 355–363.
Link
Satoh, A., K. Mitogawa and A. Makanae. 2015. Regeneration inducers in limb regeneration. Dev. Growth Differ. 57: 421–429.
PubMed Link
Singh, B. N., N. Koyano-Nakagawa, A. Donaldson, C. V. Weaver, M. G. Garry and D. J. Garry. 2015. Hedgehog signaling during appendage development and regeneration. Genes 6: 417–435.
PubMed Link
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