regeneration in nature

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Nerve-dependence in regeneration

In the field of animal regeneration an important and recurrent issue is how pivotal is the nervous system to the process. That is, does regeneration depend on any neural factor or neural influence? Based on what we know from many regenerative models it is generally assumed that the nervous system is largely required for regeneration, however, very little is known about how exactly the nervous system controls this process.  What are the molecules involved? Do these neural factors control cell proliferation? Or differentiation? Or migration? Or patterning? Or polarity? One thing that appears more or less clear is that the nature of such neural influence will not be probably electrical or transmitter-based (at least from current knowledge in amphibians).

In freshwater planarians, classical and more recent data suggest a role of the nervous system on regeneration. Thus, old experiments from Bondi (1959) and Lender and Gripon (1962) showed that during head regeneration, planarians with a very shortened ventral nerve cord on one side formed symmetrical blastemas, but the eye corresponding to the side of the longer ventral nerve cord appeared earlier than the eye of the shorter nerve cord. Other experiments by Kishida and Kurabuchi (1978) reported a delay in regeneration in fragments deprived of nerve cords. Studies from Lender (1961, 1964) and Sauzin-Monot (1972) showed the presence of an increased number of neurosecretory cells after amputation. More recently, it has been described that the silencing of Smed-roboA results in the new cephalic ganglia being disconnected of the underlying ventral nerve cords, with this disconnection giving rise to the differentiation of ectopic pharynges and dorsal outgrowths. A proposed explanation was that in the absence of proper connectivity between the brain and the ventral nerve cords, putative neurally-derived signals could be present in the surrounding tissues, altering the behaviour of the neoblasts and inducing the morphogenetic defects observed ( Also, it has been shown how the disruption of the ventral nerve cords continuity results in altered fate and axial polarity of the regenerating planarians (

One of the laboratories that has worked more on nerve-dependence in regeneration providing the most clear molecular evidences so far is the laboratory of Jeremy Brockes. In a recent review ( they discuss the current state-of-the-art of nerve-dependence regeneration. The authors revise some examples of nerve-dependence regeneration in annelids, planarians, Hydra, sea stars and mammals. In the case of the amphibian limb it is well-known since the 1950s that denervation prior to amputation blocks regeneration. However, it was only in 2007 that the laboratory of Brockes found the possible molecular basis of such nerve-dependence ( After amputation the secreted newt anterior gradient (nAG) protein is upregulated in the Schwann cells of axons near the stump. Later nAG is expressed in gland cells below the wound epithelium. Denervation prevents the expression of nAG Remarkably, ectopic expression of nAG in a denervated limb induces the expression of nAG in gland cells below the wound epithelium and is able to rescue the regenerative capability. Although it is not known how exactly nAG promotes regeneration and whether or not this rescue is directly caused by nAG or instead by any other factor regulated b y nAG, in vitro experiments suggest that nAG may promote cell proliferation.

 The fact that amphibian limb regeneration requires innervation is in contrast with what happens during embryonic development where the outgrowth of the limb does not depend on nerves. Remarkably, in amphibians it is possible to make them develop a so-called “aneurogenic” limb. For that, a section of the neural tube can be removed from the embryos so the limb develops without any innervation. Interestingly, those aneurogenic limbs are able to regenerate despite their lack of innervation. However, when those aneurogenic limbs are transplanted to a normal host, they become innervated and, from that time, their regeneration becomes nerve-dependence. In a paper published few months ago the laboratory of Brockes showed that the aneurogenic limb maintains high expression of nAG in gland cells and how, after transplantation and innervation, there is a marked downregulation of nAG expression in the epidermis ( Thus, it would be the persistent expression of nAG in the aneurogenic limbs what would allow their regeneration. On the other side, it would be then the downregulation of nAG what probably mediates the establishment of nerve-dependence for the regeneration of these aneurogenic limbs once they are innervated.

 However, nAG seems to work through Prod-1, a membrane GPI-anchored protein that appears salamander-specific. Therefore, and as the authors point out, nerve dependence will be most probably based in a variety of mechanisms. The final goal could be to ensure that the regenerated structured becomes functionally innervated. In any case, it seems clear that we need much more work, especially in non-amphibian models, first to identify the molecular basis of such nerve-dependence phenomenon and then, to be able to put it in a evolutionary context as well as in relation with other developmental programs that operate during embryogenesis or asexual reproduction.



  1. Jaume Baguñà says:

    To be fair, Kumar and Brockes review ‘Nerve dependence in tissue, organ, and appendage regeneration’ should be re-written as ‘Nerve dependence in tissue, organ, and appendage regeneration…. in amphibians’ because the bulk of the review deals with this phenomenon in this group of organisms. After two thirds of the review, some references are given to ear regeneration (???) in mammals and to nerves and the Stem Cell (SC) niche, closing with a brief ‘en passant’ references, some clearly outdated, to the role of nerves in planarian, hydra and annelid regeneration. I wished to have read a more balanced paper.

    Since Marcus Singer pioneer work back in the 1950s-60s, it is falrly well known that nerves influence regeneration, likely by activating cell proliferation and differentiation. This work was expanded to other model systems and similar findings reported. From it, the most pressing question posed was to find the molecules, substances, or whatever at the base of it. Second to it, another baffling question was, given that all animals do have nerve cords, tracts or processes, why is that some regenerate and other do not? As of today, 50 years later, we are still in the dark.

    Kumar and Brockes deals with the first problem and namely concentrate on their own work of the newt anterior gradient (nAG) protein which interact with the Prod-1 receptor, involved to confer opositional identity along the Proximal-Distal axis in amphibians. Another item they deal with is the phenomenon of aneurogenic limbs, again interpreted through nAG action. So far, so good. In the meantime, molecules as important as transferrin, Substance P (SP), GFG-2 and FGF-2, which activate FGF-1, -2 and -8 and DLX-3 at the Wound Epithelium (WE) starting the plethora of epithelial-mesenchymal interactions leading to blastema cell proliferation, are barely mentioned. Finally, I found the references to regeneration of the mammalian ear and the role of nerve terminals in the niche of mammalian stem cells interesting but in this context rather exotic.

    As far as planarians are concerned, their treatment is shallow and leaves out relevant data and people. I would like to mention the work done by french and japanese researchers between 1950s and 1970s using Dorsal-Ventral inverted grafts and the repeated severing of nerve tracts in uncut adult planarians. This work showed the role of the nervous system in producing outgrowths (hence proliferation) as well as giving rise to new heads, eyes and pharynxes (differentiation and pattern formation). Last but not least, no mention is given to biochemical and molecular biology work showing a clear role of neurotransmitters and neuropeptides to activate cell proliferation during planarian regeneration. Pity. Similar comments apply to hydra.

    This review shows again the ravages stemming from the ‘cottage industry’ of regeneration. That is, each model is dealt with in a cottage with little or no interaction with people working in cottages nearby with other model systems. It is time to shift to a global enterprise and leave for ever this ‘cottage’ attitude. I urge Kumar and Brockes to update their references.


    • The remit of a TINS article is to consider recent findings in an area, and is much closer to journals like the Current Opinion series than to Biological Reviews. We were asked by the Editor before acceptance to provide a list of the recent papers that would be the basis of the article. The aim in writing for TINS was to interest neurobiologists in these unconventional properties of nerves. The recent work on nerves in relation to the mammalian stem cell niche and tissue repair was an aspect of this, and important for acceptance by the journal. There really was limited scope for delving into earlier work.

      With respect to the point on “cottage industry”, our review on comparative aspects of regeneration for Annual Reviews (2008) is predicated on considering regeneration in different phylogenetic contexts. The issue of whether it reflects a basically unitary ancestral mechanism, or not, has been the subject of earlier blogs in this series.


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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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