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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 3

Decreased junctional integrity and increased migration of RPE cells in RPEΔMT mice.

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Decreased junctional integrity and increased migration of RPE cells in R...
(A) Immunoblot of RPE cells from pigmented RPEΔMT mice shows increased N-cadherin and reduced β-catenin. (B–I) Immunostaining of RPE flat mounts from RPEΔMT mice (C, E, G, and I) shows N-cadherin (green) substantially increased in RPE cytoplasm but diminished at cell junctions (C, arrows denote cell junctions). β-Catenin staining (green) is obscured at cre-expressing cell (red) boundaries, with a cytoplasmic redistribution (E, arrows), which is confirmed by co-labeling of β-catenin (green) and phalloidin (red) (G, arrows). (I) A stacked Z-series confocal image (15-μm thickness) shows diminished ZO1 staining (red) at RPE cell junctions. Original magnification, ×400. (J–N) Light microscopy of albino (J and K) and pigmented (L–N) RPEΔMT mice demonstrates gaps between RPE cells (J, arrows), RPE vacuoles (J–L), multilayered RPE cells (K, arrows), and numerous cells in the subretinal space (arrowheads in J–N), which leads to an uneven RPE appearance at late stages as well as RPE atrophy (boxed area in M). (N) Asterisks mark drusen-like material. (O and P) Cre-expressing RPE cells (red) are present in the subretinal space (arrowheads), whereas F4-80 reactivity (green), indicative of macrophages/microglia, is restricted to less than 2% of the RPE layer at 26 weeks. (J–P) Original magnification, ×630. (Q) An electron micrograph from an RPEΔMT mouse shows 2 pigmented cells of similar appearance (a and b), 1 of which a has migrated to the subretinal space. Original magnification, ×5000. (R) Loss of OXPHOS causes a sequence of morphological and molecular changes, beginning with a process of RPE dedifferentiation. Up and down arrows denote increased and decreased expression, repectively.

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