title: A mouse model for studying cone photoreceptor pathologies.
abstract: OBJECTIVE
  Due to the low abundance of cone photoreceptors in the mouse retina and the scarcity of alternative animal models, little is known about mechanisms of cone degeneration. Nrl knockout mice develop exclusively the cone-type of photoreceptors. However, the cone photoreceptor layer in Nrl(-/-) mice displays an irregular morphology with severe rosette formation. Retinas of Rpe65(-/-);Nrl(-/-) mice have no rosettes due to the lack of 11-cis-retinal, but also are not functional. To develop a model with a functional all-cone retina that is morphologically well structured, we generated R91W;Nrl(-/-) double-mutant mice, which express a hypomorphic Rpe65 allele (R91W).
  
  
  METHODS
  The following analyses were used to characterize the R91W;Nrl(-/-)mice: morphology by light and electron microscopy, protein distribution by immunofluorescence, cone function by electroretinography and optomotor response, RNA levels by RT-PCR, and chromophore levels by HPLC. Cone degeneration was assessed in R91W;Nrl(-/-) mice treated with MNU, and in triple R91W;Nrl(-/-);Cpfl1 and quadruple R91W;Nrl(-/-);Cpfl1;rd10 mutant mice.
  
  
  RESULTS
  The all-cone retina of R91W;Nrl(-/-) mice is functional and relatively stable with only very slow age-related degeneration. Using triple and quadruple mutant mice, or a chemical treatment, we demonstrated that cone degeneration could be induced and analyzed in these mice.
  
  
  CONCLUSIONS
  The reduced levels of visual chromophore prevented rosette formation and sustained function in the R91W;Nrl(-/-) retina. Thus, the R91W;Nrl(-/-) mouse allows study of the etiology of diseases related to cone degeneration in a "morphologically intact" and functional all-cone photoreceptor retina.
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland.
authors.forename: Marijana
authors.initials: M
authors.lastname: Samardzija
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland Center for Neuroscience, University of Zurich, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Caprara
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Severin R
authors.initials: SR
authors.lastname: Heynen
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Willcox DeParis
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meneau
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Traber
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland.
authors.forename: Cavit
authors.initials: C
authors.lastname: Agca
authors.affiliation: Case Western Reserve University, Cleveland, Ohio, United States.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004596:Electroretinography; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D012160:Retina / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology*; D012162:Retinal Degeneration / Q000473:pathology* / Q000503:physiopathology; D012172:Retinaldehyde / Q000172:deficiency; D019745:cis-trans-Isomerases / Q000378:metabolism
chemical_list: D019745:cis-trans-Isomerases; D012172:Retinaldehyde
keywords: AMD; RPE65; cone cell death; mouse model