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Axonal regeneration in zebrafish is promoted after a first lesion

In contrast to the central nervous system, peripheral axons are capable of regeneration up to different extend in many vertebrates, including mammals. Zebrafish offer the opportunity to follow this process of axonal regeneration in vivo. A recent paper from the laboratory of Alain Ghysen (http://www.ncbi.nlm.nih.gov/pubmed/24474787) describes how axonal regeneration in the posterior lateral line (PLL) occurs throughout adulthood with high fidelity, although the latency before the nerve regenerates increases with age. Noticeably, they found that regeneration is promoted after a first lesion at any age.

            The PLL is formed by neuromasts, superficial mechanosensory organs innervated by afferent neurons. Previous studies had shown how axons innervating the neuromasts were efficiently regenerated within 24h in young fishes. Here, the authors analysed whether the PLL nerve regenerates in adults. They used a reporter line in which all neurons were labelled and took advantage that PLL axons run right under the skin, so they are quite accessible for an easy imaging. They first checked axonal regeneration in juveniles at 1 mpf (month post fertilization). Remarkably, the branching pattern of the regenerated axons mimicked the original pattern. Even when the original (pre-amputated) pattern displayed some irregularity (as for example, nerve branches leaving the lateral nerve half a somite anterior or posterior to the normal branching point), these irregularities were reproduced by the regenerated axons with a high fidelity.

            Next, they studied axonal regeneration at 1, 3, 6 and 15 mpf by following how neuromasts were reinnervated after a nerve cut. The onset of reinnervation appeared to be delayed with age. This latency between nerve transection and neuromast reinnervation increased steadily with age. But on the other side, and in terms of speed of reinnervation, no differences were found between 1 and 6 mpf, as in all cases there was an almost complete regeneration within 5 days after the onset of reinnervation. However, this was not the case for fishes at 15 mpf, as in them only about 25% of the neuromasts were reinnervated in the same period. Therefore, there is an increase in latency from 1 to 15 mpf, whereas the speed of regeneration is only diminished in 15 mpf fishes.

            The authors then analysed the dynamics of regeneration after a second cut. What they did was to cut again the PLL nerve immediately posterior to the first cut and after a complete reinnervation had been achieved (at days 6, 7, 9 and 14 after the first nerve cut in 1, 3, 6 and 15 mpf fishes, respectively). They found that regeneration was successful after this second cut. Remarkably, whereas the speed of regeneration was not significantly different between the first and the second regeneration event, they observed how the latency of reinnervation (from amputation to complete regeneration) was dramatically reduced after the second cut. That is, after a second cut the reinnervation of the neuromasts was achieved faster than the first time.

            These results suggested that there could be some regeneration-promoting factor induced or derived from the first cut that would still be present by the time of the second cut, accelerating this second regenerative event. However, this acceleration of the second regeneration event took place only at a certain time after the first cut. Thus, for example, in 3 mpf fishes, regeneration was faster when the second cut was made 1 week after the first cut, but not when it was done after 3 weeks. In this last case, the latency was the same as for the first regeneration.  Next, the authors tried to characterize better the nature of this regeneration-promoting factor. They found that when the second cut was done just posterior to the first cut a faster regeneration was observed. However, when the second cut was done 2-3 somites anterior to the first one, no reduction of the latency of reinnervation was observed. These results suggested a local origin of this regeneration-promoting factor. The fact that this promoting effect was observed when the second cut was done distal rather than proximal to the first cut could suggest that it was caused by an increased attractiveness of the distal Schwann cells. However, the presence of Schwann cells distal to the cut was not strictly required for nerve regeneration (although they serve as a preferred substrate and guidance cue for the regenerating axons). Also, Schwann cells did not seem to play a role in the reduction of latency after a second cut, because a faster regenerative event was observed after a second cut even in the absence of Schwann cells over 2-3 somites distal to the first cut. Therefore, this promoting effect appeared to be most likely intrinsic to the axons.

            In summary, the authors provided evidence that PLL nerves regenerate all throughout adulthood although from 15 mpf this process slows down. Also, they showed how the latency before complete reinnervation increases steadily with age but is reduced when a second cut is made distal to the first one. This promoting effect probably involves a local change in the properties of the axons. Future experiments should help to identify the nature of this regeneration-promoting factor.

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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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