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Autophagy in zebrafish fin regeneration

Autophagy is a biological process through which cells self-degrade unnecessary or dysfunctional components. Autophagy may be important in certain contexts such as for example nutrient starvation where a minimum level of energy is required to maintain the basic functions that warranty the survival of the cells. Another context in which autophagy can be important is during the remodelling of the cytoplasm that takes place in the process of cell reprogramming. In animal models in which regeneration depends upon an initial dedifferentiation of differentiated cells into proliferative cells, an extensive cytoplasmic remodelling must occur. However, few data is available about the role that autophagy may play during regeneration. Now, a recent paper from the laboratories of DJ Klionsky and T Vellai reports on the role of autophagy in zebrafish fin regeneration (

The authors use first a transgenic line carrying a GFP reporter under the control of Lc3 promoter, a specific marker for autophagosomes and autolysosomes. They found that Lc3 was upregulated within the tail fin blastema at 2 days after amputation (dpa). From that time the levels of Lc3 gradually decreased until reaching basal levels around 6 dpa. Lc3 was expressed in newly differentiated cells within the blastema. As those cells come from dedifferentiation, Lc3 expression could be reflecting an autophagic activity during this dedifferentiation-redifferentiation process. This increase in autophagy during regeneration was further corroborated by observations of electron microscopy. Thus, an increase of autophagic features was detected in epidermal cells, osteocytes and pigment cells of 2-day blastemas.

In order to see whether this increase in autophagy had a role during regeneration the authors used different methods to block this process. They either injected an antisense morpholino oligonucleotide against atg5 or a drug that acts as an autophagy inhibitor. Silencing of atg5 at 2 dpa blocked regeneration and induced the degeneration of the existing blastema. Similar results were obtained after using the inhibitory drug. Because in other models the inhibition of autophagy induces apoptosis the authors checked next whether the defects in regeneration after blocking autophagy could be explained in terms of increased apoptosis. Indeed, an increase of apoptotic cells within the blastemas was observed. Not only apoptosis was missregulated but also they observed a significant reduction of proliferative cells as well as problems with cell differentiation. All these data lead the authors to conclude that autophagy would promote cell survival and proliferation and would mediate cell differentiation during regeneration.

Finally, the authors looked for upstream regulators of autophagy in this context. It is well known that the FGF signalling is required for fin regeneration and it silencing inhibits cell dedifferentiation. MAPK/ERK is one of the downstream effectors of FGF signalling and has been involved with the regulation of autophagy. Therefore, the authors checked whether the blocking of MAPK/ERK itself influenced fin regeneration. Using an inhibitory drug they found a complete impairment of fin regeneration. Remarkably, they also observed a decrease of autophagy in those treated animals, suggesting that MAPK/ERK activity was required for the upregulation of autophagy during regeneration. From all that data the authors propose a model in which Fgf signalling would lead to the phosphorylation of MAPK/ERK that would then regulate autophagy.

In summary, the authors conclude that autophagy would act as a prerequisite for the regeneration of the zebrafish tail fin through the regulation of the reorganization and remodelling of the cytoplasmic compartment during cell dedifferentiation.


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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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