Regulation of Müller glial reprogramming by the stress response protein REDD1 and its limitations in preventing...

Studies here investigated the role of the stress-response protein regulated in development and DNA damage response 1 (REDD1) in Müller glial reprogramming in response to sodium iodate (NaIO₃)-induced retinal degeneration. We previously demonstrated that global REDD1 deletion protected mice from NaIO₃-induced retinal damage. NaIO₃ promoted Müller glial remodeling, characterized by increased levels of glial fibrillary acidic protein (GFAP) and the horizontal orientation of Müller glial processes that localized to areas of retinal degeneration. NaIO₃ increased TGF-β1 and mesenchymal gene expression in the retina, including upregulation of N-Cadherin in Müller glia. Retinal gliosis and mesenchymal markers were reduced in the retina of REDD1-deficient mice as compared to wild-type mice after NaIO₃ administration, but this was likely secondary to retinal protection. TGF-β signaling was also investigated in human MIO-M1 Müller cell cultures. TGF-β1 increased REDD1 and the expression of gliosis and mesenchymal markers in wild-type Müller cells, and REDD1 deletion reduced TGF-β1-induced mesenchymal marker expression. REDD1 and its downstream effector GSK3β were required for TGF-β1-induced Smad2 linker domain phosphorylation and mesenchymal marker expression. To investigate the role of REDD1-dependent Müller glial reprogramming in retinal protection, NaIO₃ was administered to Müller-glia specific REDD1 knockout mice. Müller glia-specific REDD1 deletion attenuated Müller cell remodeling; however, NaIO₃-induced retinal damage was similar in Müller glia-specific REDD1 knockout and floxed control mice and visual function was only modestly preserved. The findings support the role of REDD1-dependent signaling in Müller cell reprogramming and implicate a critical role for REDD1 in cells beyond Müller glia in pathological retinal degeneration.