title: Biological characterization of gene response in Rpe65-/- mouse model of Leber's congenital amaurosis during progression of the disease.
abstract: RPE65 is the retinal isomerase essential for conversion of all-trans-retinyl ester to 11-cis-retinol in the visual cycle. Leber's congenital amaurosis (LCA), an autosomal recessive form of RP resulting in blindness, is commonly caused by mutations in the Rpe65 gene. Whereas the molecular mechanisms by which these mutations contribute to retinal disease remain largely unresolved, affected patients show marked RPE damage and photoreceptor degeneration. We evaluated gene expression in Rpe65-/- mouse model of LCA before and at the onset of photoreceptor cell death in 2, 4, and 6 month old animals. Microarray analysis demonstrates altered expression of genes involved in phototransduction, apoptosis regulation, cytoskeleton organization, and extracellular matrix (ECM) constituents. Cone-specific phototransduction genes are strongly decreased, reflecting early loss of cones. In addition, remaining rods show modified expression of genes encoding components of the cytoskeleton and ECM. This may affect rod physiology and interaction with the adjacent RPE and lead to loss of survival signals, as reflected by the alteration of apoptosis-related genes Together, these results suggest that RPE65 defect triggers an overall remodeling of the neurosensitive retina that may, in turn, disrupt photoreceptor homeostasis and induce apoptosis signaling cascade toward retinal cell death.
authors.affiliation: Institute of Research in Ophthalmology, Sion, Switzerland. sandra.cottet@iro.vsnet.ch
authors.forename: Sandra
authors.initials: S
authors.lastname: Cottet
authors.forename: Lydia
authors.initials: L
authors.lastname: Michaut
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Boisset
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schlecht
authors.forename: Walter
authors.initials: W
authors.lastname: Gehring
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001766:Blindness / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010786:Photoreceptor Cells / Q000473:pathology; D014785:Vision, Ocular / Q000235:genetics; D019745:cis-trans-Isomerases / Q000235:genetics; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C077124:retinal isomerase