regeneration in nature

Home » Amphibians » Rule of distal transformation: who obeys it and who doesn’t?

Rule of distal transformation: who obeys it and who doesn’t?

During regeneration not only missing tissues and structures are re-made but also they need to be precisely patterned and integrated along the preexisting defined body axes. Thus, in the case of axolotl limb regeneration, if you amputate at the level of the wrist, only the hand is regenerated. If you amputate through the lower arm, then a lower arm and a hand are regenerated. Finally, if you amputate at the level of the upper arm, a new upper arm, lower arm and hand regenerate. That is, only the structures distal to the amputation plane are regenerated. This is known as the rule of distal transformation. More amazingly, classical experiments showed that if a hand blastema is grafted onto a stump at the level of the upper arm, a normal limb regenerates with the hand blastema cells contributing only to the new hand.  In 2009, the laboratory of Elly Tanaka published a very important paper showing that contrary to the notion of a blastema being composed by a mass of undifferentiated cells, a more realistic view is that of a heterogeneous blastema formed by different populations of lineage-restricted progenitor cells ( In that paper they determined that during regeneration new muscle, Schwann and epidermal cells derive from preexisting muscle, Schwann and epidermal cells, respectively. New dermis and skeletal cells could derive from either pre-existing dermis or skeletal cells. The main message was then that when cells dedifferentiate and proliferate in order to provide the blastema with new cells to regenerate the missing structures they somehow keep a memory of their origin. Then, combining specific GFP labeling and grafts for different cell types and tissues they showed that cartilage cells obey the rule of distal transformation but that Schwann cells do not.

                Now, a recent paper by Nacu and collaborators from Tanaka’s lab have expanded the characterization of which cell types and tissues obey this rule ( Thus, when grafting a wrist blastema from an animal in which connective cells express GFP onto an upper arm stump of a non-labeled host, GFP positive connective cells are found only in the regenerated hand. But when the authors transplant an upper arm blastema from an animal in which connective cells express GFP onto an upper arm stump of a non-labeled host, now GFP positive cells are found in the regenerated upper arm, lower arm and hand. This indicates that connective tissue cells obey the rule of distal transformation. However, when using GFP labeled muscle cells they saw that these do not obey that rule. So, if a wrist blastema from an animal in which muscle fibers express GFP is transplanted onto an upper arm stump of a non-labeled host, GFP muscle cells are found in the upper arm, lower arm and hand. In addition to these results, the authors also provide evidences that similarly to what happens during embryonic development the β-catenin pathway appears to have a role during the patterning of the regenerated muscle tissues. This provides a new example of how some processes are regulated by the same molecules and pathways in both development and regeneration.

                In summary these results may help to characterize the main actors and processes involved in the establishment of the proximo-distal outcome of axolotl limb regeneration.



  1. Jaume Baguñà says:

    As it is with the narrow assignment of regenerating systems as either epimorphic or morphallactic, here it is a new entry into old concepts that need to be revised or simply thrown away: the rule of distal transformation. Because Biology does noy have many laws or rules (actually very few), many biologists feel the need (Physics envy others say) to extrapolate a single or a few observations into a rule or law applying to everything. This is not correct.

    Take intercalary regeneration and distal transformation. From Bohn’s experiments in cockroaches, back in the 1970s (Bohn, H. Dev Biol 53, 285-293, 1976), it is well known that intercalar blastema cells come both from proximal and distal elements. This was proven again by Truby (JEEM, now Development; 75, 151-164, 1983). In planarians, we showed (Saló and Baguñà, Roux’s Arch Dev Biol, now Dev,Genes&Evol; 194, 364-368, 1985), using head-tail (graft-host) bearing different chromosomal markers, that intercalar blastema cells giving rise to the central area (bearing the pharynx) do come both from anterior (head) and posterior (tail) fragments. I believe the list of examples contravening such a rule is very large. Therefore, let’s call it distal transformation when it is so, proximal transformation when it is like this, or just intercalar regeneration when both occur; but let’s avoid the word rule.

    As a side-comment, coining ‘rules’ in regeneration and/or in embryonic development often arise from the lack of communication between research groups working on different model systems. It is also a sort of ‘rule’ that papers dealing with amphibian regeneration usually have no references to work in hydra, planarian or annelid regeneration. The converse is usually true. In other words, ‘Regeneration people’ still work as a sort of cottage industry and not as a global enterprise. Pity.


    • I totally agree with Jaume Baguñà that more communication among researchers working on regeneration in different models would benefit the whole field. Specially, comparisons between how very different systems (vertebrate vs invertebrate, for example) regenerate. It is also true that in biology there are very few rules or laws. In the case of the “rule of distal transformation” referred to limb regeneration I think that, without entering into semantic or deeper considerations, what is an objective recurrent observation is that only those parts distal to the amputation plane are in fact regenerated. To me, another level of discussion is how this actually happens. I mean, when talking about how the tissues of the missing limb are formed and how does their patterning occur, we may ask ourselves whether that happens by intercalation, or in a proximo-distal sequence, or in a disto-proximal sequence? But the final outcome is that for an outsider observed only those parts distal to the amputation plane have been rebuilt. Is that sufficient to call it a “rule”? Maybe we could just consider as a “rule” what Ferchault de Réaumur wrote in 1712: “Nature gives back to the animal precisely and only that which it has lost, and she gives back to it all that it has lost”. Although here it could be also argued that in some circumstances animals with reduced regenerative capacities (or animals that have lost good regenerative capabilities because of aging, for example) regenerate structures that do not resemble the original ones either morphologically or functionally. But does that invalid the “rule”?
      As we all know and have heard or experienced, “there is no rule without exception” or “the exception makes the rule”.


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Francesc Cebrià

Francesc Cebrià

Francesc Cebrià

I am a Biologist and Professor at the University of Barcelona. I do my research on a fascinating animal: freshwater planarians. You can cut them in as many pieces as you want and each piece will regenerate a complete new flatworm in very few days. In this blog I will keep you updated on the latest news on the field of animal regeneration. You will be able to follow the latest research on how planarians, axolotls, newts, cnidarians and other animals are able to regenerate parts of their bodies

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