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. 1994 Feb 1;91(3):974–978. doi: 10.1073/pnas.91.3.974

Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa.

C Portera-Cailliau 1, C H Sung 1, J Nathans 1, R Adler 1
PMCID: PMC521436  PMID: 8302876

Abstract

Retinitis pigmentosa (RP) is a group of inherited human diseases in which photoreceptor degeneration leads to visual loss and eventually to blindness. Although mutations in the rhodopsin, peripherin, and cGMP phosphodiesterase genes have been identified in some forms of RP, it remains to be determined whether these mutations lead to photoreceptor cell death through necrotic or apoptotic mechanisms. In this paper, we report a test of the hypothesis that photoreceptor cell death occurs by an apoptotic mechanism in three mouse models of RP: retinal degeneration slow (rds) caused by a peripherin mutation, retinal degeneration (rd) caused by a defect in cGMP phosphodiesterase, and transgenic mice carrying a rhodopsin Q344ter mutation responsible for autosomal dominant RP. Two complementary techniques were used to detect apoptosis-specific internucleosomal DNA fragmentation: agarose gel electrophoresis and in situ labeling of apoptotic cells by terminal dUTP nick end labeling. Both methods showed extensive apoptosis of photoreceptors in all three mouse models of retinal degeneration. We also show that apoptotic death occurs in the retina during normal development, suggesting that different mechanisms can cause photoreceptor death by activating an intrinsic death program in these cells. These findings raise the possibility that retinal degenerations may be slowed by interfering with the apoptotic mechanism itself.

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Selected References

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  1. Appel S. H. A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer disease. Ann Neurol. 1981 Dec;10(6):499–505. doi: 10.1002/ana.410100602. [DOI] [PubMed] [Google Scholar]
  2. Bissonnette R. P., Echeverri F., Mahboubi A., Green D. R. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature. 1992 Oct 8;359(6395):552–554. doi: 10.1038/359552a0. [DOI] [PubMed] [Google Scholar]
  3. Bowes C., Li T., Danciger M., Baxter L. C., Applebury M. L., Farber D. B. Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature. 1990 Oct 18;347(6294):677–680. doi: 10.1038/347677a0. [DOI] [PubMed] [Google Scholar]
  4. Chang G. Q., Hao Y., Wong F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron. 1993 Oct;11(4):595–605. doi: 10.1016/0896-6273(93)90072-y. [DOI] [PubMed] [Google Scholar]
  5. Cunningham T. J. Naturally occurring neuron death and its regulation by developing neural pathways. Int Rev Cytol. 1982;74:163–186. doi: 10.1016/s0074-7696(08)61172-9. [DOI] [PubMed] [Google Scholar]
  6. Dryja T. P., Hahn L. B., Cowley G. S., McGee T. L., Berson E. L. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9370–9374. doi: 10.1073/pnas.88.20.9370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dryja T. P., McGee T. L., Reichel E., Hahn L. B., Cowley G. S., Yandell D. W., Sandberg M. A., Berson E. L. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature. 1990 Jan 25;343(6256):364–366. doi: 10.1038/343364a0. [DOI] [PubMed] [Google Scholar]
  8. Farrar G. J., Kenna P., Jordan S. A., Kumar-Singh R., Humphries M. M., Sharp E. M., Sheils D. M., Humphries P. A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa. Nature. 1991 Dec 12;354(6353):478–480. doi: 10.1038/354478a0. [DOI] [PubMed] [Google Scholar]
  9. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kajiwara K., Hahn L. B., Mukai S., Travis G. H., Berson E. L., Dryja T. P. Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature. 1991 Dec 12;354(6353):480–483. doi: 10.1038/354480a0. [DOI] [PubMed] [Google Scholar]
  11. Koike T., Martin D. P., Johnson E. M., Jr Role of Ca2+ channels in the ability of membrane depolarization to prevent neuronal death induced by trophic-factor deprivation: evidence that levels of internal Ca2+ determine nerve growth factor dependence of sympathetic ganglion cells. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6421–6425. doi: 10.1073/pnas.86.16.6421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. LaVail M. M. Analysis of neurological mutants with inherited retinal degeneration. Friedenwald lecture. Invest Ophthalmol Vis Sci. 1981 Nov;21(5):638–657. [PubMed] [Google Scholar]
  13. McLaughlin M. E., Sandberg M. A., Berson E. L., Dryja T. P. Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet. 1993 Jun;4(2):130–134. doi: 10.1038/ng0693-130. [DOI] [PubMed] [Google Scholar]
  14. Naash M. I., Hollyfield J. G., al-Ubaidi M. R., Baehr W. Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5499–5503. doi: 10.1073/pnas.90.12.5499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nichols B. E., Sheffield V. C., Vandenburgh K., Drack A. V., Kimura A. E., Stone E. M. Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene. Nat Genet. 1993 Mar;3(3):202–207. doi: 10.1038/ng0393-202. [DOI] [PubMed] [Google Scholar]
  16. Olsson J. E., Gordon J. W., Pawlyk B. S., Roof D., Hayes A., Molday R. S., Mukai S., Cowley G. S., Berson E. L., Dryja T. P. Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa. Neuron. 1992 Nov;9(5):815–830. doi: 10.1016/0896-6273(92)90236-7. [DOI] [PubMed] [Google Scholar]
  17. Pittler S. J., Baehr W. Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8322–8326. doi: 10.1073/pnas.88.19.8322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Raff M. C. Social controls on cell survival and cell death. Nature. 1992 Apr 2;356(6368):397–400. doi: 10.1038/356397a0. [DOI] [PubMed] [Google Scholar]
  19. Sanyal S., Hawkins R. K., Zeilmaker G. H. Development and degeneration of retina in rds mutant mice: analysis of interphotoreceptor matrix staining in chimaeric retina. Curr Eye Res. 1988 Dec;7(12):1183–1190. doi: 10.3109/02713688809033222. [DOI] [PubMed] [Google Scholar]
  20. Sung C. H., Davenport C. M., Hennessey J. C., Maumenee I. H., Jacobson S. G., Heckenlively J. R., Nowakowski R., Fishman G., Gouras P., Nathans J. Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6481–6485. doi: 10.1073/pnas.88.15.6481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Travis G. H., Brennan M. B., Danielson P. E., Kozak C. A., Sutcliffe J. G. Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds). Nature. 1989 Mar 2;338(6210):70–73. doi: 10.1038/338070a0. [DOI] [PubMed] [Google Scholar]
  22. Vaux D. L. Toward an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):786–789. doi: 10.1073/pnas.90.3.786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Waring P., Kos F. J., Müllbacher A. Apoptosis or programmed cell death. Med Res Rev. 1991 Mar;11(2):219–236. [PubMed] [Google Scholar]
  24. Wells J., Wroblewski J., Keen J., Inglehearn C., Jubb C., Eckstein A., Jay M., Arden G., Bhattacharya S., Fitzke F. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat Genet. 1993 Mar;3(3):213–218. doi: 10.1038/ng0393-213. [DOI] [PubMed] [Google Scholar]
  25. Wyllie A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]
  26. Young R. W. Cell death during differentiation of the retina in the mouse. J Comp Neurol. 1984 Nov 1;229(3):362–373. doi: 10.1002/cne.902290307. [DOI] [PubMed] [Google Scholar]

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