title: Cone opsin mislocalization in Rpe65-/- mice: a defect that can be corrected by 11-cis retinal.
abstract: OBJECTIVE
  In retinal degenerative diseases, rod photoreceptors typically deteriorate more rapidly than cone photoreceptors. In the Rpe65(-/-) mouse, a model for Leber's congenital amaurosis, cones degenerate much more rapidly than rods. In this model, the retinoid processing pathway in the retinal pigment epithelium is disrupted, and 11-cis retinal is not generated. This study was designed to investigate the feasibility of restoring functional cones with exogenous 11-cis retinal.
  
  
  METHODS
  Rpe65(-/-)::Rho(-/-) mice were used to remove any interference of rods and compared with wild-type (wt) mice. Pups were injected intraperitoneally with 11-cis retinal, starting at postnatal day (P)10, and were maintained in complete darkness. At P25, cone function was assessed with photopic single-flash and flicker ERGs. Cone survival was determined immunohistochemically with cone-specific antibodies, and cone opsin levels were obtained by quantitative RT-PCR.
  
  
  RESULTS
  At P25, cone density and transcript levels of cone opsins were drastically reduced, but a minute cone electroretinogram was detected, indicating that the cones were functional. Confocal microscopy revealed that the cone opsins were mislocalized, suggesting that their transport to the outer segments was impaired. Intraperitoneal administrations of 11-cis retinal before P25 led to increased transport of cone opsins to the outer segments and preserved cones anatomically and functionally.
  
  
  CONCLUSIONS
  The results suggest that the ligand is required during cone opsin synthesis for successful opsin trafficking and that without 11-cis retinal, cones may degenerate because of opsin mislocalization. These results may have important consequences for the treatment of cone dystrophies.
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, 29425, USA. rohrer@musc.edu
authors.forename: Baerbel
authors.initials: B
authors.lastname: Rohrer
authors.forename: Heather R
authors.initials: HR
authors.lastname: Lohr
authors.forename: Peter
authors.initials: P
authors.lastname: Humphries
authors.forename: T Michael
authors.initials: TM
authors.lastname: Redmond
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Rosalie K
authors.initials: RK
authors.lastname: Crouch
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins; D002470:Cell Survival; D004596:Electroretinography; D005136:Eye Proteins / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010775:Photic Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D012172:Retinaldehyde / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D017299:Rod Opsins / Q000235:genetics / Q000378:metabolism*; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D012333:RNA, Messenger; D012172:Retinaldehyde; D012243:Rhodopsin; D017299:Rod Opsins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase