title: The Thioredoxin Encoded by the Rod-Derived Cone Viability Factor Gene Protects Cone Photoreceptors Against Oxidative Stress.
abstract: Rod-derived cone viability factor long (RdCVFL) is an enzymatically active thioredoxin encoded by the nucleoredoxin-like-1 (Nxnl1) gene. The second product of the gene, RdCVF, made by alternative splicing is a novel trophic factor secreted by rods that protects cones in rodent models of retinitis pigmentosa, the most prevalent inherited retinal disease. It acts on cones by stimulating aerobic glycolysis through its interaction with a complex containing basigin-1 and the glucose transporter GLUT1. We studied the role of Nxnl1 in cones after its homologous recombination using a transgenic line expressing Cre recombinase under the control of a cone opsin promoter.
  
  
  
  We show that the cones of these mice are dysfunctional and degenerate by 8 months of age. The age-related deficit in cones is exacerbated in young animals by exposure to high level of oxygen. In agreement with this phenotype, we found that the cones express only one of the two Nxnl1 gene products, the thioredoxin RdCVFL. Administration of RdCVFL to the mouse carrying a deletion of the Nxnl1 gene in cones reduces the damage produced by oxidative stress. Silencing the expression of RdCVFL in cone-enriched culture reduces cell viability, showing that RdCVFL is a cell-autonomous mechanism of protection.
  
  
  
  This novel mode of action is certainly relevant for the therapy of retinitis pigmentosa since the delivery into cones of the rd10 mouse, a recessive model of the disease, rescues cones.
  
  
  
  Our work highlights the duality of the Nxnl1 gene, which protects the cones by two distinct mechanisms. Antioxid. Redox Signal. 24, 909-923.
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Xin
authors.initials: X
authors.lastname: Mei
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Antoine
authors.initials: A
authors.lastname: Chaffiol
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Christo
authors.initials: C
authors.lastname: Kole
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Géraldine
authors.initials: G
authors.lastname: Millet-Puel
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clérin
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Najate
authors.initials: N
authors.lastname: Aït-Ali
authors.affiliation: 4 Scheie Eye Institute, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Deniz
authors.initials: D
authors.lastname: Dalkara
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Jens
authors.initials: J
authors.lastname: Duebel
authors.affiliation: 1 INSERM , U968, Paris, France .|2 Department of Genetics, UMR_S 968, Institut de la Vision, Sorbonne Universités , Paris, France .|3 CNRS , UMR_7210, Paris, France .
authors.forename: Thierry
authors.initials: T
authors.lastname: Léveillard
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D065840:Protective Factors; D012160:Retina / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000378:metabolism; D059010:Single-Cell Analysis; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism
chemical_list: D005136:Eye Proteins; C525119:RdCVF protein, mouse; D013879:Thioredoxins