Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 May 15;89(10):4422–4426. doi: 10.1073/pnas.89.10.4422

Retinal degeneration is rescued in transgenic rd mice by expression of the cGMP phosphodiesterase beta subunit.

J Lem 1, J G Flannery 1, T Li 1, M L Applebury 1, D B Farber 1, M I Simon 1
PMCID: PMC49094  PMID: 1350091

Abstract

The beta subunit of the cGMP phosphodiesterase (PDE) gene has been identified as the candidate gene for retinal degeneration in the rd mouse. To study the molecular mechanisms underlying degeneration and the potential for gene repair, we have expressed a functional bovine cGMP PDE beta subunit in transgenic rd mice. One transgenic mouse line showed complete photoreceptor rescue across the entire span of the retina. A second independently derived line showed partial rescue in which photoreceptors in the superior but not the inferior hemisphere of the retina were rescued. In the latter animals, intermediate stages of degeneration were observed in the transition zone between rescued and diseased photoreceptors. Pathologic changes in the retina ranged from vesiculation of the basalmost outer segment discs in otherwise structurally intact rod cells to photoreceptors with highly disorganized outer segments and intact inner segments. Totally or partially rescued retinas showed a corresponding restoration of cGMP PDE activity, whereas nonrescued retinas had minimal enzyme activity, characteristic of the rd phenotype. These transgenic animals provide models for studying the molecular basis of retinal degenerative disease and conclusively demonstrate that the phenotype of rd mice is produced by a defect in the beta subunit of cGMP PDE.

Full text

PDF
4422

Images in this article

4423Image
on p.4423
4423Image
on p.4423
4424Image
on p.4424
4425Image
on p.4425

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baehr W., Devlin M. J., Applebury M. L. Isolation and characterization of cGMP phosphodiesterase from bovine rod outer segments. J Biol Chem. 1979 Nov 25;254(22):11669–11677. [PubMed] [Google Scholar]
  2. Bowes C., Danciger M., Kozak C. A., Farber D. B. Isolation of a candidate cDNA for the gene causing retinal degeneration in the rd mouse. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9722–9726. doi: 10.1073/pnas.86.24.9722. [DOI] [PMC free article] [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. Carter-Dawson L. D., LaVail M. M., Sidman R. L. Differential effect of the rd mutation on rods and cones in the mouse retina. Invest Ophthalmol Vis Sci. 1978 Jun;17(6):489–498. [PubMed] [Google Scholar]
  5. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Danciger M., Bowes C., Kozak C. A., LaVail M. M., Farber D. B. Fine mapping of a putative rd cDNA and its co-segregation with rd expression. Invest Ophthalmol Vis Sci. 1990 Aug;31(8):1427–1432. [PubMed] [Google Scholar]
  7. Danciger M., Kozak C. A., Li T., Applebury M. L., Farber D. B. Genetic mapping demonstrates that the alpha-subunit of retinal cGMP-phosphodiesterase is not the site of the rd mutation. Exp Eye Res. 1990 Aug;51(2):185–189. doi: 10.1016/0014-4835(90)90071-2. [DOI] [PubMed] [Google Scholar]
  8. Danciger M., Tuteja N., Kozak C. A., Farber D. B. The gene for the gamma-subunit of retinal cGMP-phosphodiesterase is on mouse chromosome 11. Exp Eye Res. 1989 Feb;48(2):303–308. doi: 10.1016/s0014-4835(89)80079-x. [DOI] [PubMed] [Google Scholar]
  9. Deterre P., Bigay J., Forquet F., Robert M., Chabre M. cGMP phosphodiesterase of retinal rods is regulated by two inhibitory subunits. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2424–2428. doi: 10.1073/pnas.85.8.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Farber D. B., Lolley R. N. Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science. 1974 Nov 1;186(4162):449–451. doi: 10.1126/science.186.4162.449. [DOI] [PubMed] [Google Scholar]
  11. Farber D. B., Lolley R. N. Enzymic basis for cyclic GMP accumulation in degenerative photoreceptor cells of mouse retina. J Cyclic Nucleotide Res. 1976;2(3):139–148. [PubMed] [Google Scholar]
  12. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  13. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  14. Flannery J. G., Farber D. B., Bird A. C., Bok D. Degenerative changes in a retina affected with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1989 Feb;30(2):191–211. [PubMed] [Google Scholar]
  15. Heckenlively J. R., Rodriguez J. A., Daiger S. P. Autosomal dominant sectoral retinitis pigmentosa. Two families with transversion mutation in codon 23 of rhodopsin. Arch Ophthalmol. 1991 Jan;109(1):84–91. doi: 10.1001/archopht.1991.01080010086038. [DOI] [PubMed] [Google Scholar]
  16. KARLI P., STOECKEL M. E., PORTE A. D'EG'EN'ERESCENCE DES CELLULES VISUELLES PHOTOR'ECEPTRICES ET PERSISTANCE D'UNE SENSIBILIT'E DE LA R'ETINE A LA STIMULATION PHOTIQUE. OBSERVATIONS AU MICROSCOPE 'ELECTRONIQUE. Z Zellforsch Mikrosk Anat. 1965;65:238–252. [PubMed] [Google Scholar]
  17. LASANSKY A., DE ROBERTIS E. Submicroscopic analysis of the genetic distrophy of visual cells in C3H mice. J Biophys Biochem Cytol. 1960 Jul;7:679–684. doi: 10.1083/jcb.7.4.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lem J., Applebury M. L., Falk J. D., Flannery J. G., Simon M. I. Tissue-specific and developmental regulation of rod opsin chimeric genes in transgenic mice. Neuron. 1991 Feb;6(2):201–210. doi: 10.1016/0896-6273(91)90356-5. [DOI] [PubMed] [Google Scholar]
  19. Lipkin V. M., Khramtsov N. V., Vasilevskaya I. A., Atabekova N. V., Muradov K. G., Gubanov V. V., Li T., Johnston J. P., Volpp K. J., Applebury M. L. Beta-subunit of bovine rod photoreceptor cGMP phosphodiesterase. Comparison with the phosphodiesterase family. J Biol Chem. 1990 Aug 5;265(22):12955–12959. [PubMed] [Google Scholar]
  20. NOELL W. K. Differentiation, metabolic organization, and viability of the visual cell. AMA Arch Ophthalmol. 1958 Oct;60(4 Pt 2):702–733. doi: 10.1001/archopht.1958.00940080722016. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. SIDMAN R. L., GREEN M. C. RETINAL DEGENERATION IN THE MOUSE: LOCATION OF THE RD LOCUS IN LINKAGE GROUP XVII. J Hered. 1965 Jan-Feb;56:23–29. doi: 10.1093/oxfordjournals.jhered.a107364. [DOI] [PubMed] [Google Scholar]
  23. Stone E. M., Kimura A. E., Nichols B. E., Khadivi P., Fishman G. A., Sheffield V. C. Regional distribution of retinal degeneration in patients with the proline to histidine mutation in codon 23 of the rhodopsin gene. Ophthalmology. 1991 Dec;98(12):1806–1813. doi: 10.1016/s0161-6420(91)32046-3. [DOI] [PubMed] [Google Scholar]
  24. Taketo M., Schroeder A. C., Mobraaten L. E., Gunning K. B., Hanten G., Fox R. R., Roderick T. H., Stewart C. L., Lilly F., Hansen C. T. FVB/N: an inbred mouse strain preferable for transgenic analyses. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2065–2069. doi: 10.1073/pnas.88.6.2065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zack D. J., Bennett J., Wang Y., Davenport C., Klaunberg B., Gearhart J., Nathans J. Unusual topography of bovine rhodopsin promoter-lacZ fusion gene expression in transgenic mouse retinas. Neuron. 1991 Feb;6(2):187–199. doi: 10.1016/0896-6273(91)90355-4. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES