This blog is currently on hiatus owing to work commitments. Whilst I still keep an eye on the goings on at RiAus, and contribute to the work of the good folks at eLife, little will be added to this blog for the foreseeable future. Simon Says remains open for business, albeit at a reduced capacity. Thanks for stopping by, and I hope the archive of content found here will prove to be of interest.

Monday, 18 March 2013

Monday Science: Look at his happy, happy face

IN THE beginning, there was the mouse. There was also the nematode worm (Caenorhabditis elegans), the African clawed frog (Xenopus laevis), the fruit fly (Drosophila melanogaster), thale cress (Arabidopsis thaliana) and the zebrafish (Danio rerio), and, to a lesser extent, chickens, rabbits, guinea pigs and daphnia. These were the model organisms of science. Now, it seems, there's a new member of the club.

Say hello to this chap:


Doesn't he look happy? He's an axolotl, a curious species of endangered amphibian that lives only in the lakes around Mexico City — lakes that are being threatened by pollution and competition by invasive species. Fully grown axolotls are neotenic salamanders, 'adults' that are stuck with juvenile features because they never went through metamorphosis. Other species of salamander lose their gills and move on to land as they develop, and the happy-go-lucky, flapping external gill form of the axolotl can be induced to do this by the artificial application of thyroid stimulating hormone, but in its natural environment the axolotl is content to stay in a larval state for the duration of its life. Think of it as a tadpole that has grown its legs, but never becomes a frog.

Axolotls are not a new model in science, but a recent push into research in regeneration and injury repair has seen a flurry of articles and interest in using the threatened amphibian. Because of its perpetual larval state, the axolotl is able to regenerate lost limbs, instead of forming a scar. February was a bumper month for axolotl developmental biology papers, so I picked one, and now I’m going to tell you what it said.

Axolotl limb redevelopment follows the rule of distal transformation, a rule that ensures that anything beyond a wound — the bits lopped off — grow back as they were before. That might sound obvious, but it is a far more complex form of redevelopment than forming a scar, or the continued growth of whatever tissue is present at the site of the wound.

In the process of distal transformation, lots of different types of tissues need to grow in detailed patterns: skin, nerves, muscle and the connective tissues, such as veins, arteries, tendons, ligaments and body fat. In their study, Elly Tanaka and colleagues look closely at this connective tissue and find that it, rather than muscle, is responsible for the correct order of regeneration in severed limbs. In addition, to some extent it is the connective tissue that confers identity to the regrowing limb, for it causes biological changes to an upper-arm identity regulator called MEIS in the aftermath of upper arm, but not lower arm, amputation. The same changes to MEIS happen in muscle cells but in both upper and lower arm amputation scenarios. If the muscles were in charge, the axolotl wouldn’t know whether to build half an arm, or the whole thing.

Green-expressing wrist connective
tissue cells grow from the wrist out
Next the team used a green fluorescent protein to allow the internal workings of limb regrowth to be observed. When green-expressing muscle cells were taken from the wrist of a fully grown axolotl and transplanted into the upper arm stump of a normal, though presumably upset, amputated axolotl, green muscle cells spread in both directions from the wound — into the regenerating hand, and up the arm towards the body. Next they tried again, this time using green-expressing connective tissue cells from the wrist and transplanting them on to the amputated upper arm stump. This time, green cells only spread away from the body, into the regenerating hand.

Lastly, they transplanted green-expressing connective tissue cells from the upper arm into the upper arm stump of another, non-green animal. This time, green cells were found throughout the upper and lower arms and the hands.

To summarise, muscle cells, regardless of where they come from, grow everywhere, without showing any limb identity. Connective tissue, on the other hand, grows only that which was more distal — further away from the body — than the wound, growing a hand when cells were taken from the wrist, growing all parts of the arm when cells were taken from the upper arm.

And that’s essentially all the paper has to say.

Even though its findings won’t set the world alight, I chose this paper because it is indicative of the usefulness of the axolotl as a model species in science. Their finding, that connective tissue not muscle confers identity in a regenerating limb, is just one small finding in the field of injury repair and is unlikely to garner much attention outside of the field, despite being important. Until recently, that field was quite small — the wider world didn’t pay much attention to the strange, smiling, freakish creature in the lakes of Mexico City, but now it is starting to, as if the oddity worthy of only scant attention turned out to be just what we were looking for all along. This makes me wonder what mysteries might be left to be first found, then studied, in the strange, ignored creatures that hide in plain sight? What can we learn from the monsters at the bottom of the garden, from the miniature krakens in your neighbour’s neglected pond, or from the Psammead dealing in wishes to Cyril, Anthea, Robert, Jane and the Lamb?

There is much being spoken of at present about ‘wonder’ in science. Wonder comes from the most unpredictable of places; so we must keep asking questions, and keep our eyes open at all times, else we might miss a question or an answer staring us in the face.

E. Nacu et al. Connective tissue cells, but not muscle cells, are involved in establishing the proximo-distal outcome of limb regeneration in the axolotl. Development 140, 513-518 (2013) doi:10.1242/dev.081752

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