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TNFα links apoptosis to proliferation in zebrafish retinal regeneration

Among vertebrates zebrafish display amazing regenerative capabilities as they can regrow fins, the tail and even the heart. Also, and in contrast to other vertebrates such as mammals, zebrafish can regenerate their retinal cells. Zebrafish retinal regeneration depends upon the activation of Müller glia. After damage in the retina, Müller glia dedifferentiate and re-enter the cell cycle giving rise to a cycling population of multipotent progenitors that will differentiate into the required retinal cell types.

A recent paper from the laboratory of David R. Hyde reports on the role of Tumor Necrosis Factor-Alpha 1 in this process ( Previous studies had shown that following a light-induced photoreceptor cell death there is an increase in the number of cycling Müller glia. This suggested that maybe a factor from the dying cells could activate that Müller glia re-enter the cell cycle. In fact, the injection of homogenates from light-damaged retinas into undamaged eyes is able to increase the number of cycling Müller glia. In contrast, no such increase is observed when injecting homogenates from undamaged retinas. In order to find out proteins present in those homogenates from light-damaged retinas that could activate Müller glia, the authors carried out a comparative proteomic approach. By doing this they identified more than 50 proteins expressed >2-fold in the light-damaged retinal homogenates. One of those proteins was TRAP1 (TNF receptor associated protein 1), which led to the authors check the role of the TNFa signalling pathway in the activation of Müller glia.

Upon light-induced damage the expression of TNFa increases first in apoptotic photoreceptors and later in Müller glia at the time they start to proliferate. Then, the authors carried out several experiments with morpholinos against tnfa delivered at different time points before or after the light-induced damaging of the retinas. A first conclusion of those experiments is that tnfa does not appear to be required for the initial light-induced cell death but is necessary for the activation of Müller glia at later stages of regeneration. Next the authors show that the expression of tnfa in the damaged retina is also necessary for the upregulation of Ascl1a and Stat3 in the Müller glia, which in fact appear also required for a successful regeneration.

Based on previous reports that suggested the existence of different cell subpopulations among Müller glia, the authors propose here a model in which TNFa secreted from apoptotic retinal neurons activates the expression of Ascl1a in PPMg (Primary Proliferating Müller glia). This expression of Ascl1a makes PPMg to re-enter the cell cycle and express Stat3. Then Stat3 induces the expression of tnfa in the PPMg. This new TNFa is secreted and activates the expression of Ascl1 in SPMg (Secondary Proliferating Müller glia), which, in turn, activates the proliferation of those cells. However, the exact relationships between all these different factors within the different types of Müller glia remain to be clearly elucidated.

In summary, this study identifies TNFa signalling produced by apoptotic retinal neurons as the signal that would induce Müller glia proliferation at the initiation of zebrafish retinal regeneration. These results are in agreement with those obtained from other models in which it has been shown that signals coming from apoptotic cells are required for a proper regenerative output (i.e. Hydra). Further studies should try to elucidate the exact role of apoptosis in triggering regeneration in different models and cellular and tissue contexts.

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