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bioRxiv · 10.1101/2021.10.05.463152

NFkB-signaling suppresses Müller glia-mediated neuron regeneration in the mammalian retina

Palazzo, I.·Todd, L.·Hoang, T. V.·Reh, T. A.·Blackshaw, S.·Fischer, A. J.
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Abstract

Muller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however NFkB activity is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGF{beta}2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.

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Palazzo, I., Todd, L., Hoang, T. V., Reh, T. A., Blackshaw, S., Fischer, A. J.. 2021-10-07. NFkB-signaling suppresses Müller glia-mediated neuron regeneration in the mammalian retina. https://doi.org/10.1101/2021.10.05.463152

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