Unleashing regenerative potential

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The Wnt- beta -catenin pathway is crucial to the regeneration of appendages in several vertebrates, although these regeneration-promoting properties are not only restricted to organisms that naturally regrow appendages.

The potential to replace damaged tissues, organs and appendages is obviously of great biomedical interest, but, unfortunately, not all organisms have extensive regenerative abilities. New work shows that the Wnt– beta -catenin pathway is crucial to the regeneration of appendages in several vertebrates. Remarkably, the regeneration-promoting properties of beta -catenin function are not restricted to organisms that are naturally able to regrow appendages. This molecule can also promote limb regeneration in the chick embryo, in which limb regeneration was not previously thought to occur.

The authors first showed in axolotls, Xenopus laevis and zebrafish that interfering with the Wnt pathway through infection with adenoviruses expressing antagonists such as Axin1 or Dkk1 caused defects in limb or fin regeneration. Consistent with this, expression of an activated form of beta -catenin was able to promote limb regeneration in X. laevis, and to rescue a zebrafish mutation with defective regenerative properties.

Disruption of Wnt signalling alters the formation of the apical ectodermal cap (AEC) — the multilayered epithelium that covers the wound after amputation — and this defect correlates with changes in the spatio-temporal distribution of p63. Interestingly, p63 is required in higher vertebrates for the formation of the apical ectodermal ridge (AER), a pseudostratified epithelium that, similar to the regenerating AEC, drives the proliferation of mesenchymal cells to shape the developing limb.

Given the similarities of these processes, Kawakami and colleagues used a non-regenerating animal, the chick, to investigate the role of the Wnt pathway following AER removal. They found that activated beta -catenin had the ability to rescue the expression of fgf8, a member of the fibroblast growth factor (FGF) family that is involved in limb outgrowth, and can induce the regeneration of the AER, which is essential for normal limb development.

So, regeneration in adults and tissue generation during embryonic development seem to share similar mechanisms. A further understanding of this overlap could allow regeneration to be stimulated in other tissues and structures that are not normally able to regenerate, which would have invaluable medical applications.

Francesca Pentimalli

References

Kawakami, Y. et al. Wnt/-catenin signaling regulates vertebrate limb regeneration. Genes Dev. 7, 873 - 884, (2006) | Article | PubMed |
Alvarado, A. S. & Tsonis, P. A. Bridging the regeneration gap: genetic insights from diverse animal models. Nature Rev. Genet. 7, 873–884 (2006) | Article | PubMed |