Apoptosis of Photoreceptors and Lens Fiber Cells with Cataract and Multiple Tumor Formation in the Eyes of Transgenic Mice Lacking the P53 Gene and Expressing the HPV 16 E7 Gene Under the Control of the IRBP Promoter
Because of the clinical heterogeneity of human inherited retinal degenerations, we have initiated a study to seek common themes in the pathogenesis of cell death of photoreceptors by apoptosis. The interstitial retinol binding protein (IRBP) promoter was used to drive expression of the human papilloma virus 16 (HPV 16) E7 gene in the retina and other ocular tissues in mice. The result is the death of photoreceptors as they undergo terminal differentiation. Lens fiber cells also die after a period of inappropriate proliferation and abnormal differentiation to form cataracts. Cross-breeding these transgenic mice to mice lacking the p53 gene leads to formation of several ocular tumors by one month of age if both copies of the p53 gene are missing. With one copy of the gene, the mice develop retinal tumors after a much longer latency and at a lower incidence; the tumors that do arise have lost their normal copy of the gene. The lack of the p53 gene does not eliminate apoptosis of either the retina or the lens in these transgenic mice although the rate of destruction of photoreceptors is slightly delayed. The retinal tumors apparently arise from precursors that survive amid a dying cell layer.
KeywordsHuman Papilloma Virus Retinitis Pigmentosa Fiber Cell Retinal Degeneration Photoreceptor Layer
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- 1.Li, Z-Y and Milam, A. H., 1995, Apoptosis in Retinitis Pigmentosa. This volume, p. 1–8.Google Scholar
- 9.LaVail, M.M., Unoki, K., Yasumura, D., Matthes, M.T., Yancopoulos, G.D. and Steinberg, R.H., 1992, Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light, Proc. Natl. Acad. Sci. USA. 89: 11249–11253.PubMedCentralPubMedCrossRefGoogle Scholar
- 10.Yasumura, D., Matthes, M.T., Lau, C., Unoki, K., Steinberg, R.H. and LaVail, M.M., 1995, Attempts to rescue photoreceptors with survival factors in mice with inherited retinal degenerations or constant light damage. Invest. Ophthalmol. Vis. Sci. 36: Suppl. 1. S252.Google Scholar
- 15.Al-Ubaidi, M.R., Font, R.L., Quiambao, A.B., Keener, M.J., Liou, G.I., Overbeek, P.A. and Baehr, W., (1992), Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter. J. Cell Biol. 119: 1681–1687.PubMedCrossRefGoogle Scholar
- 16.Howes, K.A., Lasudry, J.G.H., Albert, D.M. and Windle, J.J., 1994, Photoreceptor cell tumors in transgenic mice. Invest. Ophthamol Vis Sci 35: 342–351.Google Scholar
- 24.Liou, G.I., Geng, L., Al-Ubaidi, M.R., Matragoon, S., Hanten, G., Baehr, W. and Overbeek, P.A., (1990), Tissue-specific expression in transgenic mice directed by the 5′-flanking sequences of the human gene encoding interphotoreceptor retinoid-binding protein. J. Biol. Chem. 265: 8373–8376.PubMedGoogle Scholar
- 28.Fair, E.A., Borst, D.E., Chader, G.J., and Bradley, D.J., (1994), Developmental regulation of the mouse interphotoreceptor retinol binding protein gene in the fetal and post-natal eye and pineal gland. Invest. Ophthamol Vis. Sci. Suppl. 35: abstract #2199.Google Scholar