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A. Galy, T. Léveillard, J. Sahel, A. Giangrande; The RD Fly: A Genetic Model for Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2822.
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Purpose: To understand the molecular bases of Retinitis Pigmentosa, we have set up an in vivo approach using the fly animal model. Drosophila and vertebrates share functional and molecular features: i) retina is composed by cells that have similar roles; ii) light stimulus is transduced by similar pathways. More strikingly, rhodopsin mutations associated with RP have been identified in the fly ortholog gene (DmRh1) and induce severe retinal degeneration (rd). This evolutionary conservation makes it possible to use Drosophila as a genetic model system for the study of neurodegenerative diseases. We have created a transgenic fly model for one of the most severe and widespread forms of RP in humans in order to understand the molecular and cellular causes of the degeneration phenotype. We are also using the mutant transgenic line to identify genetic suppressors of retinal degeneration. Methods: Rhodopsin point mutation P23H induces degenerative phenotypes in humans and other vertebrates. We have mutagenized DmRh1 gene at the corresponding position (P37H) and created Drosophila transgenic lines expressing the wild type or the mutant protein. The effects the dominant mutation were assessed by morphological and functional assays. Degeneration was assessed by histological and immunohistological approaches using conventional, confocal and electron microscopy. A sensitive behavioural test was set up in the laboratory to measure eye activity. Results: P37H leads to progressive degeneration that is accelerated by constant light illumination. The onset of degeneration is one of the earliest so far observed in Rh1 mutations. Retinal degeneration leads to progressive blindness due to complete loss of Rh1 expressing photoreceptors. Defects in visual activity preceed any structural sign of degeneration. Transgenic lines carrying wild type Rh1 do not show degeneration, indicating that the P37H phenotype is not due to Rh1 over-expression/activation. These data allow us to use P37H Rh1 as a model for RP. Conclusions: This approach will enable us to better understand the molecular mechanisms involved in P37H induced rd. It will also facilitate the identification of factors that have a therapeutical potential in the treatment of human retinal dystrophies.
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