regeneration in nature

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Making heads in regeneration-deficient planarians

One of the many fascinating questions about regeneration is why some animals can regenerate and others not. In this sense, several times in this blog I have pointed out the importance of comparative studies between closely related species with different regenerative capabilities. Last week three independent studies from the laboratories of Phil Newmark (http://www.ncbi.nlm.nih.gov/pubmed/23883929), Jochen Rink (http://www.ncbi.nlm.nih.gov/pubmed/23883932) and Kiyokazu Agata (http://www.ncbi.nlm.nih.gov/pubmed/23883928) published in Nature, reported the recovery of head regrowth in regeneration-deficient planarians after silencing a particular signalling pathway.

Freshwater planarians are among the champions of regeneration as they can regenerate a whole animal (including a complete, functional central nervous system) from a tiny piece of their bodies. However, not all planarian species show the same regenerative competence. One striking observation is that several species can regrow a new head when amputated pre-pharyngeally (in planarians, the pharynx is located in the mid-body region), but those same animals cannot regenerate a head when amputated post-pharyngeally. So, what makes that those tail pieces cannot regenerate a new head even if bearing comparable numbers of stem cells as tail pieces from regeneration-competence species?

In order to address this question the laboratory of Phil Newmark used RNAseq to characterize those transcripts that were differentially expressed between pre-pharyngeal regeneration-proficient and post-pharyngeal regeneration-deficient tissues after amputation, in the species Procotyla fluviatilis. When analyzing the data they realized that many of the transcripts over-represented in the regeneration-deficient tissues corresponded to genes of the Wnt signaling pathway. Previous studies have shown that the Wnt/b-catenin pathway plays a pivotal role in specifying anterior versus posterior identity during planarian regeneration. Thus, the silencing of b-catenin transforms any tail blastema into a head fate. Conversely, the knockdown of an inhibitor of b-catenin (such as APC or axins) transforms any head blastema into tails. These results have been interpreted as b-catenin activity being required to specify posterior identity whereas in the absence of b-catenin anterior identity is specified. Because many Wnt ligands were over-expressed in regeneration-deficient tissues the authors hypothesized that an active Wnt/b-catenin pathway could be the responsible of blocking anterior regeneration in those post-pharyngeal tissues. To test it they simply silenced a b-catenin homologue and, amazingly, a new head regenerated from those regeneration-deficient tail pieces. These results indicate that those regeneration-deficient tissues are competent to express and unfold a head regeneration program but fail at the initial stage of re-establishment of axial polarity. This early step would be necessary to proceed with the subsequent regenerative events (blastema growth and differentiation into a new head). Conversely, an over-activation of the Wnt/b-catenin pathway (through the silencing of the pathway inhibitor APC), lead to the growth of ectopic tails from those regenerating tail pieces.

In the study by Jochen Rink’s lab they worked with the species Dendrocoelum lacteum. Similarly to what it is described for P. fluviatilis, after amputation at the post-pharyngeal level, the resulting tail pieces normally heal the wound and stem cells within it respond to amputation by increasing their proliferation. So, a blastema is initially formed but never grows and differentiates into a new head. In the case of D. lacteum the authors deep sequenced the transcriptomes at 8 eight time points of regeneration (0, 4, 12, 16, 24, 48, 72 and 120 hours) from pre-pharyngeal regeneration-competent tissues and post-pharyngeal regeneration-deficient tissues. In both cases, amputation lead to the normal upregulation of a collection of previously reported wound-response genes as well as a similar stem cell activation response. However, the authors saw how tail pieces failed to activate a set of head-specific genes while at the same time maintained the expression of tail markers. This was in sharp contrast to what happens in pre-pharyngeal regenerating tissues in which head markers were activated and the expression of tail markers was downregulated. Because what it is known about the Wnt/b-catenin pathway the authors speculated that the differences between pre-pharyngeal and post-pharyngeal regenerating pieces could be due either from inappropriate high levels of Wnt signaling and/or from insufficient Wnt inhibitory capacity. Therefore, they silenced b-catenin in tail pieces and, as a result, these were able then to regenerate a new head. Conversely, the silencing of APC gave rise to the regeneration of ectopic tails.

Finally, the work by Kiyokazu Agata and Yoshihiko Umesono followed a complete different strategy in the planarian Phagocata kawakatsui but also showed how the silencing of b-catenin rescues head regeneration from regeneration-deficient tail pieces.

In summary, the three studies show how just by simply modulating the Wnt/b-catenin signalling pathway you can transform a regeneration-deficient tissue into a regeneration-competent tissue capable then of re-growing a new head with a fully functional and complex brain. Further studies should determine why in these species the post-pharyngeal pieces, upon amputation, fail to modulate the Wnt/b-catenin pathway to re-specify proper polarity and subsequently trigger the head-regeneration program. These terribly exciting results may help us to understand the mechanisms responsible for the loss of regeneration capacities through evolution as well as provide insights into how to promote regrowth in regeneration-deficient models.

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4 Comments

  1. Jaume Baguñà says:

    Indeed, these are nice/very nice papers dealing with one of the unanswered questions in planarian regeneration. To be fair, it has to be mentioned that some years ago it was shown that Wnt injection in limbs of nonregenerating amphibians stimulated distal limb regeneration. Because distal in limbs could be made homologous to posterior at the main body axis, this makes sense (in a reverse way) with the results now published in planarians.

    However, I would like to make some comments, personally sent previously to Phil Newmark and Jochen Rink, to tune down just a little bit their results. Although fascinating, their results are stated as a black and white or all or none responses. That is, the species used regenerate heads prepharyngeally but never do it postpharyngeally. This is not really so. In the particular case of Dendrocoelum lacteum (paper by Rink et al), it is known, though not referred to in their paper, that in southern populations (South France, Spain) of D.lacteum 10-20% of specimens regenerate little heads postpharyngeally, this being related to body length (smaller animals do it better) and temperature (Romero, Baguñà and Calow; Invert.Reprod.Dev. 20:107-113 (1991)). In contrast, northern populations (England, Sweden), like those used by Rink et al, never regenerate heads postpharyngeally. One has to wonder, irrespectively that levels of Wnt-ß-cat are likely involved in both populations, on the causes of such differences. The most likely answer, whatever it turns out to be, could lie on differences in life-cycle strategies between them. Northern populations are semelparous (breed once and die); southern populations are iteroparous (breed yearly and live for several years). Hence, differences in energy partitioning between somatic cell turnover and reproductive output between these populations (very evident indeed; Romero and Baguñà; Fortschr. Zool. 36, 283-289 (1988)) may be the selective force behind them.

    In summary. Regeneration responses are not white or black, but go along a spectrum from all to nothing. To those interested in this subject, I suggest to look at Figure 19 (page 30) of Bronsted book ‘Planarian Regeneration’ (Pergamon Press, 1969) where head-frequencies of different planarian species-groups are depicted. The variety is bewildering and might prompt some to deepen on the causes behind it.

    This is like asexual reproduction, sometimes featured as a yes or no feature. In my favourite species, Schmidtea mediterranea, the asexual race of which I found and described in Barcelona in the 1970s, very large specimens (over 20mm in length) developed ovaries, testes, follicle cells, all the copulatory apparatus, and layed infertile egg capsules (cocoons). Similarly, very large (over 15mm in length) specimens of the asexual race of Girardia tigrina, also developed all attributes for sexual reproduction. To say nothing of the common ex-fissiparous specimens of many european continental freshwater planarian species (namely those of the Dugesia group). Interesting, isn’t it?

    In any case, well done. Very nice papers.

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  2. Debra Baker says:

    The abstracts look interesting now to get my hands upon the full texts.

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  3. Reblogged this on Baldscientist and commented:
    The august 1, 2013 issue of the journal “Nature” featured papers from three independent research groups that threw some light on the question “… why are some planarians species better at regeneration than others?” I will soon post a layperson-friendly translation of these papers. (:-)

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  4. Excellent! I will reblog this at “Baldscientist” and as we discussed I will soon write a layperson translation summarizing the papers.

    Like

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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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