title: Genetic background and light-dependent progression of photoreceptor cell degeneration in Prominin-1 knockout mice.
abstract: OBJECTIVE
  Mutations in the Prominin-1 (Prom1) gene are known to cause retinitis pigmentosa and Stargardt disease, both of which are associated with progressive photoreceptor cell death. There are no effective therapies for either disorder. The aim of this study was to investigate the mechanism of the retinal degeneration in Prom1-deficient mouse models.
  
  
  METHODS
  We constructed Prom1 knockout mice with two distinct genetic backgrounds of C57BL/6 and C57BL/6xCBA/NSlc, and investigated the photoreceptor degeneration by means of histology and functional tests.. In addition, we examined the effect of light on the Prom1(-/-) retina by rearing the mice in the normal light/dark cycle and completely dark conditions. Finally, we investigated if the retinoic-acid derivative Fenretinide slowed the pace of retinal degeneration in these mouse models.
  
  
  RESULTS
  The Prom1(-/-)-knockout mice with both backgrounds developed photoreceptor degeneration after eye opening, but the CB57/BL6-background mice developed photoreceptor cell degeneration much faster than the C57BL/6xCBA/NSlc mice, demonstrating genetic background dependency.. Interestingly, our histologic and functional examination showed that the photoreceptor cell degeneration of Prom1-knockout mice was light-dependent, and was almost completely inhibited when the mutant mice were kept in the dark. The Prom1-knockout retina showed strong downregulation of expression of the visual cycle components, Rdh12 and Abca4. Furthermore, administration of Fenretinide, which lowers the level of the toxic lipofuscin, slowed the degeneration of photoreceptor cells.
  
  
  CONCLUSIONS
  These findings improve our understanding of the mechanism of cell death in Prominin-1-related disease and provide evidence that fenretinide may be worth studying in human disease.
authors.affiliation: Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Dellett
authors.affiliation: Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sasai
authors.affiliation: Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology (CDB), Kobe, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nishide
authors.affiliation: Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Silke
authors.initials: S
authors.lastname: Becker
authors.affiliation: Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Papadaki
authors.affiliation: Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: G Astrid
authors.initials: GA
authors.lastname: Limb
authors.affiliation: Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology (CDB), Kobe, Japan Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Ocular Biology and Therapeutics Unit (ORBIT), Faculty of Brain Sciences, UCL Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Ohnuma
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004596:Electroretinography; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009154:Mutation; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000648:ultrastructure*; D060888:Real-Time Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D004247:DNA
keywords: Prominin-1; Stargardt disease; fenretinide; light; modifier gene; photoreceptor degeneration; retinitis pigmentosa