The pallid marvel of regeneration

Axolotls are able to regenerate not only their limbs but also their eyes and even parts of their heart in just a few weeks. Now international scientists have succeeded in sequencing the salamander’s full genome.
 

“Never really grew up” is a characterization that some adults have to live with until they “act their age.” For Mexican axolotls (Ambystoma mexicanum) this is no metaphor but reality. The approximately 25 cm long colorless salamanders actually spend their entire lives in a gill breathing, larval stage underwater. Owing to a congenital thyroid defect, the little critters do not undergo any metamorphosis but nevertheless achieve sexual maturity.

What makes axolotls special, however, is their extreme regenerative capacity. If the animals lose a body part, it takes them just a few weeks to regenerate a perfect replacement including bones, muscles and nerves in situ. Even a full-grown axolotl has the capacity to regrow a severed leg, its entire tail, a section of jaw, a severed spinal cord, a missing eye or even parts of the heart, in the space of a few weeks. Researchers assume a marked penchant toward cannibalism to be a key reason for an axolotl’s extreme regenerative capacity. Regrowing bitten-off limbs and nerves would appear to be a crucial evolutionary advantage for this approximately 350 million year old species of amphibian.

Ten times the size of the human genome

To better understand axolotl’s regenerative capacity, scientists needed to know the full DNA sequence. But the axolotl’s genome makes for a particular challenge, because at 32 billion base pairs it eclipses the human genome by a factor of at least ten. It also features a substantial number of long, repeating sequences, which further complicate research. An international research team, led by Elly Tanaka of the Research Institute for Molecular Pathology in Vienna, Eugene W. Myers of the Max-Planck Institute in Dresden and Siegfried Schloissnig of the Heidelberg Institute for Theoretical Studies (HITS), has nevertheless recently managed to fully sequence the axolotl’s genome. Researchers reported in “Nature” at the beginning of the year that it is the largest genome to have been decoded for a terrestrial organism.

This work relies on the development of a new sequencing technology (PacBio method), which is able to read some further 72 million longer portions of the genome. Individual pieces of the sequence were recombined like a jigsaw puzzle. Analyzing the data revealed some of the axolotl’s peculiarities. For instance, they lack an important and prevalent developmental gene called PAX3; the function of which has been taken up by the related gene PAX7. Both genes play a key role in building muscles and nerves.

Genetic map with full details

Humans have stem cells theoretically capable of regenerating many organs, like liver, fat and muscle stem cells. But in the course of evolution, mammals have almost completely lost this ability. If axolotls can easily regrow new limbs and organs, why shouldn’t regeneration work for us? In decoding the axolotl’s genome, we hope to have made a small step toward answering this question, as the sequence of the base pairs harbors the information for the salamander’s extreme regenerative capacity. “At our disposal we now have a genetic map which we can use to probe how complex structures such as legs can be regrown,” explained Sergej Nowoshilow, IMP postdoc and the study’s lead author. But even with this knowledge, we are still a long way from solving the puzzle, as only complex interaction between many control centers in the body enables organs to regenerate. It will be the job of young scientists such as Nowoshilow to find the right switches and understand their interaction. Because we are currently seeing such substantial progress, he can imagine that we will be far enough along in “20 or 30 years” to be able to regrow limbs.

The axolotl, to which we owe so much, is unfortunately facing a difficult future in the volcanic lakes of Mexico. The animal is on the United Nations’ red list of endangered species. Estimates from the year 2009 indicate there are only 700 to 1200 of these animals left in the wild - far fewer than those in research laboratories.
 

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