Organ and Appendage Regeneration in the Axolotl

  • Johanna E. Farkas
  • Piril Erler
  • Polina D. Freitas
  • Alexandra E. Sweeney
  • James R. MonaghanEmail author


Regeneration is a remarkable feat of biology. It requires an organ system – most often consisting of many different cell types – to stop its specialized function and step back in ontological time. Regeneration overcomes the general understanding that development is a one-way street. We now know that there is great variability in regeneration capacity across phylogeny, likely because animals need to have some mechanism in place to survive injuries or diseases that it will encounter. Some animals, including humans, meet this need by closing the wound as quickly as possible and making due with the deficit. Other animals, such as the axolotl described here, instead regenerate the damaged or missing tissue.

Ambystoma mexicanum, commonly known as the axolotl, is uncommon among vertebrates because of its superior regenerative abilities. References of their unique abilities cross from the scientific to the main stream media, but they are also useful animals for understanding the mechanisms that regulate regeneration. As axolotls are tetrapods that can breed all year-round and accept grafts between adults, they possess some major advantages that make them uniquely suited to be animal models of regeneration. In terms of appendage regeneration, there is currently a lack of animal models for complex regeneration. The two dominant models are zebrafish, which regenerate caudal fins throughout life, and Xenopus frogs, which can regenerate limbs and tails early in development. Although these systems have provided important insights into vertebrate regeneration, the axolotl limb is particularly well suited to study adult appendage regeneration. Axolotls are capable of regenerating complete adult limbs that are morphologically similar to human limbs using endochondral ossification. In contrast, the zebrafish dermal caudal fin skeleton has no mammalian counterpart, and the fin skeleton regenerates by direct ossification from mature osteocytes (Sousa et al. Development, 138(18):3897–3905, 2011; Knopf et al. Dev Cell 20(5):713–724, 2011). Xenopus regenerates early in development, but its ability to regenerate patterned skeletal structures is absent in adulthood. Therefore, the axolotl is among the best vertebrate models for adult joint regeneration.

Although axolotls have been studied for almost 200 years, only recently have technological advances helped revive the axolotl into a model organism in modern regeneration biology (Voss et al. Cold Spring Harbor Protoc 2009(8), 2009). The axolotl is becoming a chosen model for regenerative biology because it can regenerate more completely than any other vertebrate in the majority of organs studied. Modern genomic tools are available including microarray analysis (Monaghan et al. J Neurochem 101(1):27–40, 2007; BMC Biol 7, 2009; Biol Open. 2012; Campbell et al. Dev Dyn: An Off Publ Am Assoc Anat 240(7):1826–1840, 2011), RNAseq (Monaghan et al. BMC Biol 7, 2009; Stewart et al. PLoS Comput Biol 9(3):e1002936, 2013; Knapp et al. PLoS One 8(5):e61352, 2013), a genomic map (Smith et al. Genetics 171(3):1161–1171, 2005a), genomic sequence data (Smith et al. BMC Genomics 10:19, 2009), and bioinformatic databases (Smith et al. BMC Genomics 6:181, 2005b). Functional testing of genes is also available through the generation of transgenics (Sobkow et al. Dev Biol 290(2):386–397, 2006; Monaghan and Maden, Dev Biol 368(1):63–75, 2012a; Khattak et al. Nat Protoc 9(3):529–540, 2014; Whited et al. Proc Natl Acad Sci U S A 109(34):13662–13667, 2012), knock-down of genes by morpholinos (Schnapp et al. Development 132(14):3243–3253, 2005; Zhu et al. Dev Biol 370(1):42–51, 2012), over-expression of genes by electroporation (Mercader et al. Development 132(18):4131–4142, 2005) and viruses (Whited et al. Development 140(5):1137–1146, 2013; Khattak et al. BMC Dev Biol 13:17, 2013), and cell tracking by tissue grafting between GFP and white axolotls (Nacu et al. Cold Spring Harbor Protoc 2009(8), 2009). With this array of modern tools, married with the qualities that have made the axolotl a subject of research for hundreds of years, the axolotl system has become a powerful model to dissect the mechanisms that regulate development and regeneration.

Here, we will highlight what is known about the axolotl’s regenerative abilities and discuss the mechanisms that regulate regeneration of each organ system. It is generally assumed that the axolotl has the ability to regenerate most if not all of its tissues, but a survey of tissue regeneration has yet to be performed in this animal model. We will focus upon the regenerative capacity of the axolotl, but it is necessary to include examples of regeneration in the newt, Xenopus laevis, and zebrafish because in some aspect these species have been studied in more detail than in the axolotl model.


Axolotl Ambystoma mexicanum Cardiac regeneration Nervous system Limb regeneration Spinal cord Wound healing Immune system Extracellular matrix 


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Johanna E. Farkas
    • 1
  • Piril Erler
    • 1
  • Polina D. Freitas
    • 1
  • Alexandra E. Sweeney
    • 1
    • 2
  • James R. Monaghan
    • 1
    Email author
  1. 1.Department of BiologyNortheastern UniversityBostonUSA
  2. 2.School of Life Sciences, Queen’s Medical CentreNottingham UniversityNottinghamUK

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