AUTHOR=Iribarne Maria , Hyde David R. , Masai Ichiro 

TITLE=TNFα Induces Müller Glia to Transition From Non-proliferative Gliosis to a Regenerative Response in Mutant Zebrafish Presenting Chronic Photoreceptor Degeneration

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2019.00296

DOI=10.3389/fcell.2019.00296

ISSN=2296-634X

ABSTRACT=<p>Unlike mammals, zebrafish have the capacity to regenerate neurons in response to damage. Most zebrafish retinal injury models employ acute damage, which is unlike the chronic, gradual damage that occurs in human retinal diseases. Here, we studied the regenerative response in the zebrafish <italic>aipl1b</italic> mutant, <italic>gold rush</italic> (<italic>gosh</italic>). In <italic>gosh</italic> mutants, both cones and rods degenerate by 3 weeks post-fertilization (wpf). Müller glia do not exhibit a regenerative response by 3 wpf; however, they do present non-proliferative gliosis. Only at 5 wpf, is proliferation of Müller cells and rod precursor cells activated. Rods start to recover at 5 wpf and by 12 wpf they reach a level of recovery comparable to wild type, but cones remain absent in the adult stage. TNFα was detected in degenerating cones at 5–7 wpf and in Müller glia at 7 wpf in <italic>gosh</italic> mutants. At 5 wpf, proliferating Müller glia express Sox2, followed by Pax6 expression in neuronal progenitor cells (NPCs), confirming that the neuronal regeneration program is activated in <italic>gosh</italic> mutants after 5 wpf. Although acute light-induced damage did not activate proliferation of Müller glia, TNFα injection caused Müller glia to commence a proliferative response at 3 wpf in <italic>gosh</italic> mutants. These results suggest that Müller glia transition from non-proliferative gliosis to a regenerative state in <italic>gosh</italic> mutants, and that ectopic introduction of TNFα promotes this Müller cell transition even at 3 wpf. Thus, zebrafish <italic>gosh</italic> mutants provide a useful model to investigate mechanisms underlying retinal regeneration in a chronic photoreceptor degeneration model.</p>