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Evidence for two apoptotic pathways in light-induced retinal degeneration

Nature Genetics volume 32, pages 254–260 (2002)Cite this article

Abstract

Excessive phototransduction signaling is thought to be involved in light-induced and inherited retinal degeneration. Using knockout mice with defects in rhodopsin shut-off and transducin signaling, we show that two different pathways of photoreceptor-cell apoptosis are induced by light. Bright light induces apoptosis that is independent of transducin and accompanied by induction of the transcription factor AP-1. By contrast, low light induces an apoptotic pathway that requires transducin. We also provide evidence that additional genetic factors regulate sensitivity to light-induced damage. Our use of defined mouse mutants resolves some of the complexity underlying the mechanisms that regulate susceptibility to retinal degeneration.

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Figure 1: Phototransduction defects in animal models of retinal light damage.
Figure 2: Bright light–induced photoreceptor-cell death in retinas of albino Gnat1−/− and wildtype mice.
Figure 3: Gnat1−/− and wildtype mice are susceptible to acute damage by high-intensity light.
Figure 4: High-intensity light accelerates the induction of AP-1 in Rhok−/− Sag−/− mice relative to wildtype and Gnat1−/− mice.
Figure 5: Rhok−/− Sag−/− mice are extremely susceptible to light damage.
Figure 6: Nucleosome release is reduced in Rhok−/− and Sag−/− mice lacking transducin.
Figure 7: Absence of Gnat1 preserves the ONL in Rhok−/− and Sag−/− mice exposed to low-intensity light.
Figure 8: Absence of c-fos does not protect Rhok−/− mice from photoreceptor-cell apoptosis induced by low-intensity light, and absence of Gnat1 does not protect mice from damage induced by bright light.

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References

  1. Reme, C.E., Grimm, C., Hafezi, F., Marti, A. & Wenzel, A. Apoptotic cell death in retinal degenerations. Prog. Retinal Eye Res. 17, 443–464 (1998).

    Article  CAS  Google Scholar 

  2. Chen, J., Simon, M.I., Matthes, M.T., Yasumura, D. & LaVail, M.M. Increased susceptibility to light damage in an arrestin knockout mouse model of Oguchi disease (stationary night blindness). Invest. Ophthalmol. Vis. Sci. 40, 2978–2982 (1999).

    CAS  PubMed  Google Scholar 

  3. Chen, C.K. et al. Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. Proc. Natl Acad. Sci. USA 96, 3718–3722 (1999).

    Article  CAS  Google Scholar 

  4. LaVail, M.M., Gorrin, G.M., Yasamura, D. & Matthes, M.T. Increased susceptibility to constant light in nr and pcd mice with inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 40, 1020–1024 (1999).

    CAS  PubMed  Google Scholar 

  5. Organisciak, D.T., Li, M., Darrow, R.M. & Farber, D.B. Photoreceptor cell damage by light in young Royal College of Surgeons rats. Curr. Eye Res. 19, 188–196 (1999).

    Article  CAS  Google Scholar 

  6. Wang, M., Lam, T.T., Tso, M.O. & Naash, M.I. Expression of a mutant opsin gene increases the susceptibility of the retina to light damage. Vis. Neurosci. 14, 55–62 (1997).

    Article  Google Scholar 

  7. Grimm, C. et al. Protection of Rpe65-deficient mice identifies rhodopsin as a mediator of light-induced retinal degeneration. Nature Genet. 25, 63–66 (2000).

    Article  CAS  Google Scholar 

  8. Sieving, P.A. et al. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc. Natl Acad. Sci. USA 98, 1835–1840 (2001).

    Article  CAS  Google Scholar 

  9. Wenzel, A., Reme, C.E., Williams, T.P., Hafezi, F. & Grimm, C. The Rpe65 Leu450Met variation increases retinal resistance against light-induced degeneration by slowing rhodopsin regeneration. J. Neurosci. 21, 53–58 (2001).

    Article  CAS  Google Scholar 

  10. Keller, C., Grimm, C., Wenzel, A., Hafezi, F. & Reme, C. Protective effect of halothane anesthesia on retinal light damage: inhibition of metabolic rhodopsin regeneration. Invest. Ophthalmol. Vis. Sci. 42, 476–480 (2001).

    CAS  PubMed  Google Scholar 

  11. Fain, G.L. & Lisman, J.E. Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis. Exp. Eye Res. 57, 335–340 (1993).

    Article  CAS  Google Scholar 

  12. Fain, G.L. & Lisman, J.E. Light, Ca2+, and photoreceptor death: new evidence for the equivalent-light hypothesis from arrestin knockout mice. Invest. Ophthalmol. Vis. Sci. 40, 2770–2772 (1999).

    CAS  PubMed  Google Scholar 

  13. Lisman, J. & Fain, G. Support for the equivalent light hypothesis for RP. Nature Med. 1, 1254–1255 (1995).

    Article  CAS  Google Scholar 

  14. Noell, W.K. & Albrecht, R. Irreversible effects of visible light on the retina: role of vitamin A. Science 172, 76–80 (1971).

    Article  CAS  Google Scholar 

  15. Calvert, P.D. et al. Phototransduction in transgenic mice after targeted deletion of the rod transducin α-subunit. Proc. Natl Acad. Sci. USA 97, 13913–13918 (2000).

    Article  CAS  Google Scholar 

  16. Stryer, L. Cyclic GMP cascade of vision. Annu. Rev. Neurosci. 9, 87–119 (1986).

    Article  CAS  Google Scholar 

  17. Rapp, L. & Williams, T. in The Effects of Constant Light on Visual Processes (eds Williams, T.P. and Baker, B.N.) 135–159 (Plenum, New York, 1980).

    Book  Google Scholar 

  18. Rapp, L. & Williams, T. The role of ocular pigmentation in protecting against light damage. Vision Res. 20, 1127–1131 (1980).

    Article  CAS  Google Scholar 

  19. LaVail, M.M. & Gorrin, G.M. Protection from light damage by ocular pigmentation: analysis using experimental chimeras and translocation mice. Exp. Eye Res. 44, 877–889 (1987).

    Article  CAS  Google Scholar 

  20. Portera-Cailliau, C., Sung, C.-H., Nathans, J. & Alder, R. Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc. Natl Acad. Sci. USA 91, 974–978 (1994).

    Article  CAS  Google Scholar 

  21. Chang, G.-Q., Hao, Y. & Wong, F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron 11, 595–605 (1993).

    Article  CAS  Google Scholar 

  22. Wenzel, A. et al. Prevention of photoreceptor apoptosis by activation of the glucocorticoid receptor. Invest. Ophthalmol. Vis. Sci. 42, 1653–1659 (2001).

    CAS  PubMed  Google Scholar 

  23. Wenzel, A. et al. c-fos controls the 'private pathway' of light-induced apoptosis of retinal photoreceptors. J. Neurosci. 20, 81–88 (2000).

    Article  CAS  Google Scholar 

  24. Danciger, M. et al. A QTL on distal chromosome 3 that influences the severity of light-induced damage to mouse photoreceptors. Mamm. Genome 11, 422–427 (2000).

    Article  CAS  Google Scholar 

  25. Redmond, T.M. et al. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nature Genet. 20, 344–351 (1998).

    Article  CAS  Google Scholar 

  26. Bentrop, J. Rhodopsin mutations as the cause of retinal degeneration. Classification of degeneration phenotypes in the model system Drosophila melanogaster. Acta Anat. 162, 85–94 (1998).

    Article  CAS  Google Scholar 

  27. Alloway, P.G., Howard, L. & Dolph, P.J. The formation of stable rhodopsin–arrestin complexes induces apoptosis and photoreceptor cell degeneration. Neuron 28, 129–138 (2000).

    Article  CAS  Google Scholar 

  28. Kiselev, A. et al. A molecular pathway for light-dependent photoreceptor apoptosis in Drosophila. Neuron 28, 139–152 (2000).

    Article  CAS  Google Scholar 

  29. Dillon, J., Gaillard, E.R., Bilski, P., Chignell, C.F. & Reszka, K.J. The photochemistry of the retinoids as studied by steady-state and pulsed methods. Photochem. Photobiol. 63, 680–685 (1996).

    Article  CAS  Google Scholar 

  30. Gal, A., Apfelstedt-Sylla, E., Janecke, A.R. & Zrenner, E. Rhodopsin mutations in inherited retinal dystrophies and dysfunctions. Prog. Retinal Eye Res. 16, 51–79 (1997).

    Article  CAS  Google Scholar 

  31. Khani, S.C., Nielsen, L. & Vogt, T.M. Biochemical evidence for pathogenicity of rhodopsin kinase mutations correlated with the Oguchi form of congenital stationary night blindness. Proc. Natl Acad. Sci. USA 95, 2824–2827 (1998).

    Article  CAS  Google Scholar 

  32. Nakazawa, M., Wada, Y. & Tamai, M. Arrestin gene mutations in autosomal recessive retinitis pigmentosa. Arch. Ophthalmol. 116, 498–501 (1998).

    Article  CAS  Google Scholar 

  33. Yamada, T. et al. 1147delA mutation in the arrestin gene in Japanese patients with Oguchi disease. Ophthal. Genet. 20, 117–120 (1999).

    Article  CAS  Google Scholar 

  34. Yamamoto, S., Sippel, K.C., Berson, E.L. & Dryja, T.P. Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness. Nature Genet. 15, 175–178 (1997).

    Article  CAS  Google Scholar 

  35. Cruickshanks, K.J., Klein, R., Klein, B.E. & Nondahl, D.M. Sunlight and the 5-year incidence of early age-related maculopathy: The Beaver Dam Eye Study. Arch. Ophthalmol. 119, 246–250 (2001).

    CAS  PubMed  Google Scholar 

  36. Cruickshanks, K.J., Klein, R. & Klein, B.E. Sunlight and age-related macular degeneration. The Beaver Dam Eye Study. Arch. Ophthalmol. 111, 514–518 (1993).

    Article  CAS  Google Scholar 

  37. Mata, N.L., Weng, J. & Travis, G.H. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc. Natl Acad. Sci USA 97, 7154–7159 (2000).

    Article  CAS  Google Scholar 

  38. Obin, M. et al. Calorie restriction modulates age-dependent changes in the retinas of Brown Norway rats. Mech. Ageing Dev. 114, 133–147 (2000).

    Article  CAS  Google Scholar 

  39. LaVail, M.M., Gorrin, G.M., Repaci, M.A., Thomas, L.A. & Ginsberg, H.M. Genetic regulation of light damage to photoreceptors. Invest. Ophthalmol. Vis. Sci. 28, 1043–1048 (1987).

    CAS  PubMed  Google Scholar 

  40. Hafezi, F., Marti, A., Grimm, C., Wenzel, A. & Reme, C.E. Differential DNA binding activities of the transcription factors AP-1 and Oct-1 during light-induced apoptosis of photoreceptors. Vision Res. 39, 2511–2518 (1999).

    Article  CAS  Google Scholar 

  41. Leist, M. et al. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-α requires transcriptional arrest. J. Immunol. 153, 1778–1788 (1994).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Danciger for help determining leucine/methionine polymorphism in Rpe65; D. Brunelle for help with graphics and manuscript preparation; F. Celestin of the SCOR in Ischemic Heart Disease Histology Core for assistance with histological sections; and D. Greuter, C. Imsand and G. Hoegger for technical assistance. Support for this research was provided by the US National Institutes of Health (J.L., M.I.S. and M.S.O.), Foundation Fighting Blindness (J.L.), Massachusetts Lions Eye Research Fund (an institutional grant to the Department of Ophthalmology, New England Medical Center) and Research to Prevent Blindness Special Scholar's Award (J.L.). C.E.R. received support from the Swiss National Science Foundation, German Research Council and Velux Foundation.

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Author notes

  1. Wenshan Hao, Andreas Wenzel, Martin S. Obin and Ching-Kang Chen: These authors contributed equally to this work.

  2. Charlotte E. Remé and Janis Lem: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biology, California Institute of Technology, Pasadena, 91125, California, USA

    Wenshan Hao, Ching-Kang Chen, Pamela Eversole-Cire & Melvin I. Simon

  2. Laboratory of Retinal Cell Biology, University Hospital Zurich, Zurich, CH-8091, Switzerland

    Andreas Wenzel, Christian Grimm & Charlotte E. Remé

  3. Nutrition and Vision Research Laboratory, JMUSDA-HNRCA at Tufts University, Boston, 02111, Massachusetts, USA

    Martin S. Obin & Allen Taylor

  4. Department of Ophthalmology and Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, 02111, Massachusetts, USA

    Elliott Brill, Nataliia V. Krasnoperova & Janis Lem

  5. Program in Genetics, Tufts University School of Medicine, Boston, 02111, Massachusetts, USA

    Yelena Kleyner & Janis Lem

  6. Department of Oncology, Wyeth Research, Pearl River, 10965, New York, USA

    Wenshan Hao & Ching-Kang Chen

  7. Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, 84112, USA

    Wenshan Hao & Ching-Kang Chen

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Correspondence to Janis Lem.

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Hao, W., Wenzel, A., Obin, M. et al. Evidence for two apoptotic pathways in light-induced retinal degeneration. Nat Genet 32, 254–260 (2002). https://doi.org/10.1038/ng984

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