Reprogramming of adult rod photoreceptors prevents retinal degeneration

• DOI: 10.1073/pnas.1214387110
• Publication Date: 2013-01-15T04:55:05Z
• Authors: Cynthia L. Montana; Alexander V. Kole...; Susan Q. Shen; Connie A. Myers; Vladimir J. Kefalov; Joseph C. Corbo
• Keywords: Mice, Knockout; 0301 basic medicine; Rhodopsin; Reverse Transcriptase Polymerase Chain Reaction; Retinal Degeneration; Gene Expression; DNA Methylation; Immunohistochemistry; Retina; 3. Good health; Mice, Inbred C57BL; Mice; Microscopy, Electron; 03 medical and health sciences; Basic-Leucine Zipper Transcription Factors; Retinal Rod Photoreceptor Cells; Electroretinography; Retinal Cone Photoreceptor Cells; Animals; CpG Islands; Eye Proteins; In Situ Hybridization; Retinitis Pigmentosa

A prime goal of regenerative medicine is to direct cell fates in a therapeutically useful manner. Retinitis pigmentosa is one of the most common degenerative diseases of the eye and is associated with early rod photoreceptor death followed by secondary cone degeneration. We hypothesized that converting adult rods into cones, via knockdown of the rod photoreceptor determinant Nrl , could make the cells resistant to the effects of mutations in rod-specific genes, thereby preventing secondary cone loss. To test this idea, we engineered a tamoxifen-inducible allele of Nrl to acutely inactivate the gene in adult rods. This manipulation resulted in reprogramming of rods into cells with a variety of cone-like molecular, histologic, and functional properties. Moreover, reprogramming of adult rods achieved cellular and functional rescue of retinal degeneration in a mouse model of retinitis pigmentosa. These findings suggest that elimination of Nrl in adult rods may represent a unique therapy for retinal degeneration.