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mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice
Chen Zhao, … , Matthew M. LaVail, Douglas Vollrath
Chen Zhao, … , Matthew M. LaVail, Douglas Vollrath
Published December 6, 2010
Citation Information: J Clin Invest. 2011;121(1):369-383. https://doi.org/10.1172/JCI44303.
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Research Article Ophthalmology Article has an altmetric score of 4

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

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Abstract

Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress.

Authors

Chen Zhao, Douglas Yasumura, Xiyan Li, Michael Matthes, Marcia Lloyd, Gregory Nielsen, Kelly Ahern, Michael Snyder, Dean Bok, Joshua L. Dunaief, Matthew M. LaVail, Douglas Vollrath

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Figure 6

Activation of the PI3K/AKT/mTOR pathway and increased biomass in RPEΔMT RPE.

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Activation of the PI3K/AKT/mTOR pathway and increased biomass in RPEΔMT ...
(A–D) Immunoblot detects elevated phosphorylation of (A) PI3K (p85Tyr458), AKTSer473, and GSK-3βSer9; (B) TSC2Thr1462; (C) mTORSer2448; and (D) P70SK6Thr389 and S6Ser235/236 in pooled RPE cells from pigmented RPEΔMT mice at 14 weeks, compared with that in controls. (E–H) Original magnification, ×200. (E–L) Immunostaining of retinal sections (E–H, K, and L) and RPE flat mounts (I and J) shows increased reactivity of phosphorylated AKTSer473 (F, green), mTORSer2448 (H and J, green), and S6Ser235/236 (L, green) in cre-expressing RPE cells (red/purple) in albino RPEΔMT mice. Phalloidin staining of RPE flat mounts (I and J, white) outlines cell boundaries. Original magnification, ×630. (K and L) Original magnification, ×200. (M) Protein content is increased in RPE cells of RPEΔMT mice (triplicate assays). §P < 0.01; #P < 0.001. (N and O) Oil red O staining detects a remarkable accumulation of neutral lipid in 14-week-old RPEΔMT RPE (O, purple), compared with that of a control (N). (P) Confocal microscopy of an RPEΔMT flat mount reveals autofluorescent deposits (arrows) visible over a broad spectrum of excitation wavelengths (e.g., 350, 488, and 633 nm). The deposits are initially visible at 350 nm but bleach rapidly, leading to their orange appearance in the merged picture (arrows). The flat mount was stained with anti–β-catenin (green), which highlights RPE cell boundaries at 488 nm. (Q) A higher magnification Z-stack image of the red boxed area in P. Note that autofluorescent deposits are below β-catenin (green) and therefore inside RPE cells. (P and Q) Original magnification, ×200. (R) Electron micrographs of RPEΔMT RPE reveal abundant structures consistent with lipid-containing granules (arrows). Original magnification, ×5000. (S) Funduscopy shows white deposits in a pigmented RPEΔMT mouse. Original magnification, ×50.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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