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Understanding the Regenerating Salamander: Testing the Limb-its of Regeneration

The axolotl (Ambystoma mexicanum) is a salamander best known for its remarkable regenerative capabilities. It is able to regenerate complex anatomical structures such as limbs and the spinal cord. This ability has prompted decades of research into the mechanisms governing the vertebrate body-part regeneration, yielding valuable insight into the molecular actors involved in this phenomenon. Since many of these molecular actors and their relevant processes tend to be conserved among tetrapods, axolotl research is inspired in part by the eventual application of its molecular findings to human disease and medicine (1).

Notwithstanding its worth, the axolotl is a model organism that poses many challenges to researchers who choose to work with it. This organism is unique among vertebrates in its ability to regenerate body parts, but it also possesses the longer generation time typical of vertebrates relative to other commonly-used model organisms. After fertilization, axolotls take 10-12 months to develop and become sexually mature (2). This generation time requires important considerations regarding the length of research projects that use axolotl. Such considerations can be especially important for trainees who choose to be involved in this field. For example, the long generation times affect the efficiency of breeding axolotl transgenic lines that can be used in research; thus far, only a few axolotl transgenic lines have been developed.  

In addition to the challenging generation time, the axolotl genome has yet to be sequenced. One drawback of the absence of a sequenced genome is that without a sequenced genome,  researchers are hindered from capitalizing on standard bioinformatics techniques that enable an assessment of the efficacy of genome editing technologies. For example, the efficiency and efficacy of the booming CRISPR/Cas9 genome-editing technology is affected by potential off-target sites: genomic sites that can be mistakenly targeted using the technology (3). With a sequenced genome,  researchers can anticipate off-target mutagenesis through a simple computer search. However, without a sequenced genome, it is difficult to anticipate off-target sites. Similarly, many sequencing-based molecular biology techniques are not feasible without a sequenced genome, such as chromatin immunoprecipitation sequencing (ChIP-seq), a method used to detect DNA binding sites of proteins (4).

Researchers have recognized the challenges of the axolotl model and, in light of the field’s potential, have made efforts to overcome them. Recently, in an effort taken by Jessica Whited’s group at Brigham and Women’s Hospital (Boston, MA, USA), tissue-specific transcriptome profiles for axolotls were assembled and annotated (5). This transcriptome map serves as a step forward in allowing for a broader usage of biotechnological techniques on these animals.

Regardless of the challenges along the way, research on axolotl is progressing towards a critical understanding of the mechanisms of limb development and regeneration. This understanding could, one day, be translated to humans. Nonetheless, it is important to distinguish hype from reality. Alex Wall, a former intern at the Whited Lab, warns against imprudently extending the findings in axolotl to humans, stating that “findings of genes that are important to axolotl limb regeneration do not mean that amputees will be cured anytime soon.” The potential of axolotl research is exciting, however, it is essential to be aware of the challenges in this field in order to effectively address them.

With many thanks to Alex Wall, for his wonderful reflection on his work with axolotl.

[1] McCusker, C., & Gardiner, D. M. (2011). The axolotl model for regeneration and aging research: a mini-review. Gerontology, 57(6), 565-571.

[2] Prescott, D. M. (1966). Methods in Cell Physiology: Volume 2. New York and London: Academic Press.

[3] Zhang, X. H., Tee, L. Y., Wang, X. G., Huang, Q. S., & Yang, S. H. (2015). Off-target effects in CRISPR/Cas9-mediated genome engineering. Molecular Therapy-Nucleic Acids, 4, e264.

[4] Johnson, D. S., Mortazavi, A., Myers, R. M., & Wold, B. (2007). Genome-wide mapping of in vivo protein-DNA interactions. Science, 316(5830), 1497-1502.

[5] Bryant, D. M., Johnson, K., DiTommaso, T., Tickle, T., Couger, M. B., Payzin-Dogru, D., … & Bateman, J. (2017). A tissue-mapped axolotl de novo transcriptome enables identification of limb regeneration factors. Cell reports, 18(3), 762-776.

Ghazal Haddad has been a part of SSSCR since 2014. She is the Founder and former President of the University of Toronto SSSCR (UofT-SSSCR). Currently, she works as the Community Service Chair for the UofT-SSSCR and is a member of the SSSCR-International Executive Committee. Ghazal is a senior at the University of Toronto majoring in Molecular Genetics and Immunology. She has the most fun when dancing, coding, reading, or doing research.

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