Elly Tanaka

The axolotl (Ambystoma mexicanum), with its delicate, feathery gills and pale, translucent skin, looks a bit like something from a sci-fi movie. Most wild axolotls do not look quite so ethereal, having dark, speckled skin, but when used in the lab, strains lacking dark pigments make it easier for researchers to visualise processes within the animals. Axolotls, including the pale strains, have been cultivated in the lab since the 1860s. While important for studying development and evolution, they are most famous for their regenerative abilities: if an axolotl loses a limb, it will grow back within weeks. Axolotls can even regenerate parts of their central nervous system and other internal organs.

Elly Tanaka first began studying limb regeneration as a postdoc with Jeremy Brockes at University College London, using the eastern newt (Notophthalmus viridescens) as a model organism. When she started her own lab at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden in 1999, she switched to the axolotl, quickly becoming a global authority on axolotl regeneration. Elly was Director of the Center for Regenerative Therapies Dresden when, in 2015, the IMP contacted her with an offer to join the institute. At the time, her group was pursuing several ambitious projects, including deciphering the axolotl genome, which is unusually large (ten times larger than the human genome) and full of repeated sequences. When Elly accepted the IMP’s offer, she was delighted that more than ten of her lab members decided to join her in Vienna. Relocating the axolotls was an additional challenge. “Moving a lab means a huge uprooting for people, but also for the work. There was an amazing effort at the IMP to re-establish the axolotl system, which was completely new to the institute”, Elly says.

And so, in 2016, the Tanaka lab and their axolotls took up residence at the IMP. By then, the team and their collaborators had completed most of the long-read sequencing required to decode the axolotl genome. However, due to its size and repetitiveness, assembling the genome proved to be a mammoth task. To tackle this, Siegfried Schloissnig, from the Heidelberg Institute for Theoretical Studies, developed a new genome assembler called MARVEL. Sergej Nowoshilow and Ji-Feng Fei were also key players in the project and had moved with Elly from Dresden. Sergej focused on functionally annotating the genome, while Ji-Feng developed the methodology to perform gene editing in axolotl. By combining the Tanaka lab’s established expertise with the support from IMP – which included new computational resources to analyse the giant genome – the team was able to hit the ground running. Within two years, they had the genome published (Nowoshilow et al., Nature 2018). Not only was it the largest genome ever assembled, but it was also a game-changer for regeneration research. Finally, it was possible to fully harness advanced molecular tools to study regeneration-related genes and pathways.

One such molecular tool was single-cell RNA sequencing, which, as applied to tracking development, was named by Science as “Breakthrough of the Year” in 2018. The Tanaka group collaborated with Barbara Treutlein’s team, who had been leading advances in single-cell technology applications, to tackle a long-standing regeneration mystery. While scientists knew that fibroblasts formed much of the limb blastema (the mass of cells from which the limb regrows), it remained unclear whether rare stem cells were present among the fibroblasts or if the fibroblasts themselves dedifferentiated to an embryonic-like state. To distinguish between these possibilities, they needed to track and profile individual cells. Postdoc Prayag Murawala had spent years making the transgenic axolotls that would allow them to follow individual cells using fluorescent markers. Combining these strains with single-cell sequencing, the researchers tracked cell identities in regenerating limbs. “Using dense time courses, we definitively showed that cells with adult fibroblast phenotypes transform into cells with transcriptional signatures almost identical to those of embryonic limb bud cells”, Elly explains. Thus, no special stem cells are required to regrow axolotl limbs – ordinary fibroblasts can do the trick (Gerber et al., Science 2018).

Unfortunately, these same fibroblasts in mammals form scars upon injury. This then raised the question: In non-regenerative animals, are fibroblasts prevented from dedifferentiation by external signals, or are they intrinsically unable to dedifferentiate? To address this, the researchers turned to frogs, which can regenerate as tadpoles but not after metamorphosis. PhD student Tzi-Yang Lin transplanted adult frog fibroblasts into a frog limb bud and showed that the cells could not fully reactivate the limb bud progenitor programme, indicating an intrinsic limitation (Lin et al., Dev Cell 2021). This was such a fundamental finding that it even made its way into Gilbert’s Developmental Biology textbook – the gold standard in the field.

In parallel with these discoveries, the Tanaka group had been collaborating with several other groups to sequence another huge genome: that of the Australian lungfish, which is approximately 14 times the size of the human genome. Lungfish are the closest living relatives to the animals that gave rise to land vertebrates and, like salamanders, have impressive regeneration capabilities. Siegfried, who had since moved from Heidelberg to join Elly’s lab, adapted MARVEL to assemble the genome. He recalls a particularly challenging publication process, not least because another team was also sequencing a lungfish genome. It was a close race, but their hard work was rewarded with a Nature paper (Meyer et al., Nature 2021). The other lungfish genome – that of the African lungfish – followed hot on its heels and was published in Cell just a couple of weeks later. Together with the genomes of other organisms, the axolotl and lungfish genomes provided a rich resource to study the vertebrate land invasion and the evolution of regeneration. Both lungfish and axolotl genomes contain many transposable elements, and Elly believes that these non-coding sequences are involved in regulating regeneration.

While this link remains to be explored, the Tanaka group has recently shown how chromatin, another key player in gene regulation, influences regeneration. Using genome-wide chromatin profiling in axolotl fibroblasts (only possible with the genome sequence), they uncovered distinct chromatin marks in different limb segments. This explains how positional information is encoded, providing a molecular blueprint that guides limb regeneration (Kawaguchi et al., Dev Cell 2024).

Although much of Elly’s work during her time at the IMP focused on limb regeneration, her group also studied spinal cord, brain, and eye regeneration. Given their interest in strategies to regenerate or replace mammalian tissues, they did not limit their research to the axolotl. Indeed, one of the last projects completed at the IMP investigated how neural tissues can self-organise from mouse embryonic stem cells (Krammer et al., Dev Cell 2024).

In 2024, Elly took up the directorship of IMBA, which is next door to the IMP. “I’ve moved, but not very far”, she says with a laugh. She is happy to remain closely connected to the IMP while her group continues to investigate the fundamental nature of regeneration and the potential implications for human medicine.

First published in 2025.

References

The axolotl genome and the evolution of key tissue formation regulators.
Nowoshilow S, Schloissnig S, Fei JF, Dahl A, Pang AWC, Pippel M, Winkler S, Hastie AR, Young G, Roscito JG, Falcon F, Knapp D, Powell S, Cruz A, Cao H, Habermann B, Hiller M, Tanaka EM, Myers EW; Nature 2018

Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration.
Gerber T, Murawala P, Knapp D, Masselink W, Schuez M, Hermann S, Gac-Santel M, Nowoshilow S, Kageyama J, Khattak S, Currie JD, Camp JG, Tanaka EM, Treutlein B; Science 2018

Giant lungfish genome elucidates the conquest of land by vertebrates.
Meyer A, Schloissnig S, Franchini P, Du K, Woltering JM, Irisarri I, Wong WY, Nowoshilow S, Kneitz S, Kawaguchi A, Fabrizius A, Xiong P, Dechaud C, Spaink HP, Volff JN, Simakov O, Burmester T, Tanaka EM, Schartl M; Nature 2021

Fibroblast dedifferentiation as a determinant of successful regeneration.
Lin TY, Gerber T, Taniguchi-Sugiura Y, Murawala P, Hermann S, Grosser L, Shibata E, Treutlein B, Tanaka EM; Dev Cell 2021

A chromatin code for limb segment identity in axolotl limb regeneration.
Kawaguchi A, Wang J, Knapp D, Murawala P, Nowoshilow S, Masselink W, Taniguchi-Sugiura Y, Fei JF, Tanaka EM; Dev Cell 2024

Mouse neural tube organoids self-organize floorplate through BMP-mediated cluster competition.
Krammer T, Stuart HT, Gromberg E, Ishihara K, Cislo D, Melchionda M, Becerril Perez F, Wang J, Costantini E, Lehr S, Arbanas L, Hörmann A, Neumüller RA, Elvassore N, Siggia E, Briscoe J, Kicheva A, Tanaka EM; Dev Cell 2024