Abstract
Adult urodeles (salamanders) are unique in their ability to regenerate complex organs perfectly. The recently developed Accessory Limb Model (ALM) in the axolotl provides an opportunity to identify and characterize the essential signaling events that control the early steps in limb regeneration. The ALM demonstrates that limb regeneration progresses in a stepwise fashion that is dependent on signals from the wound epidermis, nerves and dermal fibroblasts from opposite sides of the limb. When all the signals are present, a limb is formed de novo. The ALM thus provides an opportunity to identify and characterize the signaling pathways that control blastema morphogenesis and limb regeneration. Our previous study provided data on cell contribution, cell migration and nerve dependency indicating that an ectopic blastema is equivalent to an amputation-induced blastema. In the present study, we have determined that formation of both ectopic blastemas and amputation-induced blastemas is regulated by the same molecular mechanisms, and that both types of blastema cells exhibit the same functions in controlling growth and pattern formation. We have identified and validated five marker genes for the early stages of wound healing, dedifferentiation and blastema formation, and have discovered that the expression of each of these markers is the same for both ectopic and amputation-induced blastemas. In addition, ectopic blastema cells interact coordinately with amputation-induced blastema cells to form a regenerated limb. Therefore, the ALM is appropriate for identifying the signaling pathways regulating the early events of tetrapod limb regeneration.
Highlights
Adult urodeles are unique in their ability to regenerate complex organs perfectly
The results of the present study provide molecular and functional validation of the Accessory Limb Model (ALM; Endo et al, 2004) for understanding the mechanisms regulating outgrowths that can be induced in response to injury; an amputation-induced blastema, an ectopic blastema that will not form a new limb, and an ectopic blastema that will form a new limb
A lateral wound can be induced to form an ectopic limb in response to a deviated nerve and a contralateral skin graft, it previously was not known whether an ectopic limb was formed using the same molecular mechanisms that regulate regeneration of an amputated limb
Summary
Adult urodeles (salamanders) are unique in their ability to regenerate complex organs perfectly. Given the conservation of genetic mechanisms among vertebrates, it is likely that the cellular and molecular processes that regulate urodele limb regeneration are shared among all vertebrates. Since other vertebrates do not exhibit the same extent of organ regeneration, presumably these basic regenerative mechanisms are not activated in response to injury. An understanding of how urodele regenerative mechanisms are regulated will be directly applicable to understanding how to induce an enhanced regenerative response in other verte-
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