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A novel (and unknown) mechanism for dendrite regeneration in Drosophila

A successful functional regeneration of the nervous system could have a major social impact. Unfortunately, most animals, including mammals, do not regenerate well the central nervous system. However, some regenerative abilities are seen in the peripheral nervous system of flies, nematodes and mammals. After axon injury a cascade of signals travels from the injury site to the cell body triggering a regenerative response that results in axonal regrowth. An important aspect that is mainly unknown is whether dendrites (also quite sensitive to different damage situations) are able to respond to injury as axons do. Now, a paper from the laboratory of Melissa Rolls reports that, in Drosophila, dendrites can efficiently regenerate and do it through an unknown molecular mechanism different from the one used by axons (

            Previous studies had suggested that dendrites regenerated only in certain neurons at specific developmental stages. Here, the authors used a pulsed UV laser to remove all dendrites from different types of dendritic arborization (da) neurons. First, they removed all the dendrites from larval ddaE neurons. After 48h a newly regenerated branched dendrite arbor was found in almost half of the samples. Although the final area of the body wall covered by the regenerated dendrites was smaller than in controls, the complexity of those regenerated dendrite arbors in terms of the number of dendrite branch points was equivalent to controls. Next, they checked ddaC neurons. Similarly to what was observed for ddaE neurons, after 24h some processes started to grow. After 96h regeneration was completed and the new dendritic arbors covered the same area of the body wall as in controls.

In order to see if these regrown processes were real dendrites the authors followed several approaches. First, they checked microtubule polarity in those regrown neurites.  Whereas axons contain plus-end-out microtubules, dendrites are distinguished by the presence of minus-end-out microtubules. This has been observed in Drosophila, C. elegans and mammals. After 48h of regeneration the neurites regrown from severed ddaC neurons contained minus-end-out microtubules, suggesting that those neurites were real dendrites. Additionally, the authors used an Apc2-GFP marker, specific for dendrite branch points and found that this marker was localized in the regrown processes. In a final experiment the authors checked the effect of dynein on dendrite regeneration. It is known that dynein is required for the development of dendrites. Consequently, and as predicted, dynein RNAi affected dendrite regeneration. Taking in account all these results the authors concluded that after dendrite removal these different neurons were able to regenerate new dendrites. Moreover, and importantly, the authors also show how dendrite regeneration was successful not only at early larval stages but also in late larval and adult neurons.

After axonal injury an important player to trigger a regenerative response is DLK, a dual leucine zipper kinase. In several models (flies, nematodes, mammals) DLK (a MPAKKK) is activated after injury and subsequently activates cJun N-terminal kinase (JNK), p38 and the transcription factor fos. In order to see if this conserved signalling cascade required for axonal regeneration played a role also during dendrite regeneration the authors used RNAi and mutants to inhibit the levels of DLK in their model. Surprisingly, whereas axonal regeneration was impaired as expected, dendrite regeneration was not affected in those same da neurons. Finally, the authors show how dominant-negative forms of JNK or fos did not block dendrite regeneration. Thus, DLK/JNK pathway was not required for dendrite regeneration. Remarkably, this pathway was not even activated after dendrite removal.

In summary, this paper shows how dendrite from different neuronal types can regenerate in both larva and adult flies. This dendrite regeneration takes place using a novel unknown mechanism different from the conserved pathway activated during axonal regeneration in different models. Future experiments should try to determine how dendrite regeneration is triggered at the molecular level and whether this mechanism has been conserved in other animals.      

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