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Cynthia L. Montana, Joseph C. Corbo; Partial Reprogramming of Adult Mouse Rods Into Cones Rescues Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3940.
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Recent studies have demonstrated a remarkable degree of plasticity within adult mammalian cell types: fibroblasts can be converted into iPS cells and some differentiated cell types can be directly transformed into others. We wished to determine whether adult rod photoreceptors could be directly converted into cones. If this were possible, it might serve as a gene-independent approach to therapy for retinitis pigmentosa, since converting rods into cones might make the cells resistant to the effects of mutations in rod-specific genes. To test this idea, we took advantage of the fact that the photoreceptor transcription factor Nrl acts as a cell fate switch during retinal development: photoreceptor precursors that turn on Nrl become rods while those that do not become cones.
We created a mouse line containing a floxed Nrl allele and crossed it to a drug-inducible Cre recombinase-expressing line. Nrl was acutely deleted in these mice at an adult stage and retinas were evaluated several weeks later for evidence of rod-to-cone conversion.
Extensive experimental characterization of these mice showed evidence of partial reprogramming of rods into cones: many rod genes were markedly downregulated and some cone gene were derepressed. However, reprogramming was incomplete in that many cone genes, including the cone opsins, failed to be expressed in the reprogrammed rods. Next, we tested whether partial reprogramming of rods into cones might make the cells immune to the effects of a rod-specific mutation. Remarkably, we found that acute elimination of Nrl from adult rods can effect significant cellular and functional rescue in the Rho-/- mutant mouse.
Acute Nrl knockdown in the adult retina can rescue retinal degeneration in the Rho-/- mouse. Studies in other retinal degeneration mutants are ongoing. In addition, efforts are underway to overcome the genetic and epigenetic barriers to complete reprogramming of rods into cones.
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