Regulation of Müller glial reprogramming by the stress response protein REDD1 and its limitations in preventing retinal degeneration
- 1Department of Cell and Biological Systems, Penn State College of Medicine, Hershey, Pennsylvania, USA
- 2Department of Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania, USA
Abstract
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.
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BibTeX
@article{subrahmanian2026regulation,
title = {{Regulation of Müller glial reprogramming by the stress response protein REDD1 and its limitations in preventing retinal degeneration}},
author = {Sandeep M. Subrahmanian and Siddharth Sunilkumar and Shreshty Budakoti and Esma I. Yerlikaya and Allyson L. Toro and Alistair J. Barber and Michael D. Dennis},
journal = {The Journal of Biological Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.jbc.2026.113583},
url = {https://doi.org/10.1016/j.jbc.2026.113583},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regulation of Müller glial reprogramming by the stress response protein REDD1 and its limitations in preventing retinal degeneration
AU - Sandeep M. Subrahmanian
AU - Siddharth Sunilkumar
AU - Shreshty Budakoti
AU - Esma I. Yerlikaya
AU - Allyson L. Toro
AU - Alistair J. Barber
AU - Michael D. Dennis
PY - 2026
DA - 2026/09/23
JO - The Journal of Biological Chemistry
DO - 10.1016/j.jbc.2026.113583
UR - https://doi.org/10.1016/j.jbc.2026.113583
AB - 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.
SN - 0021-9258
SN - 1083-351X
ER -