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Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

Published online by Cambridge University Press:  13 February 2006

KENNETH A. LINBERG ,
ROBERT N. FARISS ,
JOHN R. HECKENLIVELY ,
DEBORA B. FARBER  and
STEVEN K. FISHER
KENNETH A. LINBERG
Affiliation:
Neuroscience Research Institute, University of California, Santa Barbara, California
ROBERT N. FARISS
Affiliation:
Neuroscience Research Institute, University of California, Santa Barbara, California Current Address of Robert N. Fariss: Biological Imaging Core, NEI-NIH, Bethesda, MD 20892-0703, USA
JOHN R. HECKENLIVELY
Affiliation:
The Jules Stein Eye Institute, Los Angeles, California Harbor-UCLA Medical Center, Torrance, California Current Address of John R. Heckenlively: Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA
DEBORA B. FARBER
Affiliation:
The Jules Stein Eye Institute, Los Angeles, California The Molecular Biology Institute, UCLA, Los Angeles, California
STEVEN K. FISHER
Affiliation:
Neuroscience Research Institute, University of California, Santa Barbara, California Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California
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Abstract

Retinal development in 3 strains of rd-3/rd-3 mutant mice, previously shown to have different rates of degeneration, was studied using light, electron, and immunofluorescence microscopy. The time course and phenotype of the degeneration as well as details on the mechanism of massive photoreceptor cell loss are compared with other known retinal degenerations in mice. Up until postnatal day (P) 10, the retinas of all three strains (RBF, 4Bnr, In-30) develop similarly to those of pigmented and nonpigmented controls. TUNEL-positive cells appear in the outer nuclear layer (ONL) by P14, and reach a maximum in all three mutant strains around P21. Scattered rods and cones form a loose, monolayered ONL by 8 weeks in the albino RBF strain, by 10 weeks in the albino 4Bnr strain, and by 16 weeks in the pigmented In-30 strain. Though the initial degeneration begins in the central retina, there is no preferred gradient of cell death between central and peripheral photoreceptors. Rods and cones are present at all ages examined. During development, stacks of outer segments (OS) form in all three strains though they never achieve full adult lengths, and often have disorganized, atypical OS. Rod opsin is expressed in the developing OS but is redistributed into plasma membrane as OS degeneration proceeds. Retinal pigment epithelial (RPE) cells of all mutant strains contain packets of phagocytosed OS, and their apical processes associate with the distal ends of the OS. At their synaptic sites, photoreceptor terminals contain ribbons apposed to apparently normal postsynaptic triads. As photoreceptors are lost, Müller cells fill in space in the ONL but they do not appear to undergo significant hypertrophy or migration, though during the degeneration, glial fibrillary acidic protein (GFAP) expression is gradually upregulated. Macrophage-like cells are found frequently in the subretinal space after the onset of photoreceptor apoptosis. As OS disappear, the RPE apical processes revert to simple microvilli. Late in the degeneration, some RPE cells die and neighboring cells appear to flatten as if to maintain confluence. In regions of RPE cell loss that happen to lie above retina where the ONL is gone, cells of the inner nuclear layer (INL), wrapped by Müller cell processes, may front directly on Bruch's membrane.

Keywords

Inherited retinal degenerationApoptosisPhotoreceptors
Type
Research Article
Information
Visual Neuroscience , Volume 22 , Issue 6 , November 2005 , pp. 721 - 734
Copyright
© 2005 Cambridge University Press

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References

REFERENCES

Blanks, J.C., Mullen, R.J., & LaVail, M.M. (1982). Retinal degeneration in the pcd cerebellar mutant mouse. II. Electron microscopic analysis. Journal of Comparative Neurology 212, 231–246.Google Scholar
Bok, D. & Hall, M. (1971). The role of the pigment epithelium in the etiology of inherited retinal dystrophy in the rat. Journal of Cell Biology 49, 664–682.Google Scholar
Bora, N., Defoe, D., & Smith, S.B. (1999). Evidence of decreased adhesion between the neural retina and retinal pigmented epithelium of the Mitfvit (vitiligo) mutant mouse. Cell and Tissue Research 295, 65–75.Google Scholar
Caley, D.W., Johnson, C., & Liebelt, R.A. (1972). The postnatal development of the retina in the normal and rodless CBA mouse: A light and electron microscopic study. American Journal of Anatomy 133, 179–212.Google Scholar
Carter-Dawson, L.D. & LaVail, M.M. (1979). Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. Journal of Comparative Neurology 188, 245–262.Google Scholar
Carter-Dawson, L.D., LaVail, M.M., & Sidman, R.L. (1978). Differential effect of the rd mutation on rods and cones in the mouse retina. Investigative Ophthalmology and Visual Science 17, 489–498.Google Scholar
Chang, B., Bronson, R.T., Hawes, N.L., Roderick, T.H., Peng, C., Hageman, G.S., & Heckenlively, J.R. (1994). Retinal degeneration in motor neuron degeneration: A mouse model of ceroid lipofuscinosis. Investigative Ophthalmology and Visual Science 35, 1071–1076.Google Scholar
Chang, B., Hawes, N.L., Hurd, R.E., Davisson, M.T., Nusinowitz, S., & Heckenlively, J.R. (2002). Retinal degeneration mutants in the mouse. Vision Research 42, 517–525.Google Scholar
Chang, B., Heckenlively, J.R., Hawes, N.L., & Roderick, T.H. (1993a). New mouse primary retinal degeneration (rd-3) linked to chromosome 1 distal to Akp-1. Genomics 16, 45–49.Google Scholar
Chang, G.-Q., Hao, Y., & Wong, F. (1993b). Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron 11, 595–605.Google Scholar
Cook, B., Lewis, G.P., Fisher, S.K., & Adler, R. (1995). Apoptotic photoreceptor degeneration in experimental retinal detachment. Investigative Ophthalmology and Visual Science 36, 990–996.Google Scholar
Danciger, J.S., Danciger, M., Nusinowitz, S., Rickabaugh, T., & Farber, D.B. (1999). Genetic and physical maps of the mouse rd3 locus, exclusion of the ortholog of USH2A. Mammalian Genome 10, 657–661.Google Scholar
Eisenfeld, A.J., Bunt-Milam, A.H., & Sarthy, P.V. (1984). Müller cell expression of glial fibrillary acidic protein after genetic and experimental photoreceptor degeneration in the rat retina. Investigative Ophthalmology and Visual Science 25, 1321–1328.Google Scholar
Erickson, P.A., Fisher, S.K., Anderson, D.H., Stern, W.H., & Borgula, G.A. (1983). Retinal detachment in the cat: The outer nuclear layer and outer plexiform layers. Investigative Ophthalmology and Visual Science 24, 927–942.Google Scholar
Farber, D.B., Flannery, J.G., & Bowes-Rickman, C. (1994). The rd mouse story: seventy years of research on an animal model of inherited retinal degeneration. Progress in Retinal Research 13, 31–64.Google Scholar
Fariss, R.N., Molday, R.S., Fisher, S.K., & Matsumoto, B. (1997). Evidence from normal and degenerating photoreceptors that two outer segment integral membrane proteins have separate transport pathways. Journal of Comparative Neurology 387, 148–156.Google Scholar
Fariss, R.N., Linberg, K.A., Lo, G.J., Heckenlively, J.R., Peng, C., & Fisher, S.K. (1994). Retinal degeneration in the rd-3 mouse leads to changes in the immunolocalization of Müller cell and photoreceptor proteins. Investigative Ophthalmology and Visual Science 35, (ARVO Supplement) 1610.Google Scholar
Finnemann, S.C. & Rodriguez-Boulan, E. (1999). Macrophage and retinal pigment epithelium phagocytosis: Apoptotic cells and photoreceptors compete for αvβ3 and αvβ5 integrins, and protein kinase C regulates αvβ5 binding and cytoskeletal linkage. Journal of Experimental Medicine 190, 861–874.Google Scholar
Fisher, S.K., Anderson, D.H., Erickson, P.A., Guérin, C.J., Lewis, G.P., & Linberg, K.A. (1993). Light and electron microscopy of vertebrate photoreceptors including a technique for electron microscopic autoradiography. Methods in Neuroscience 15, 3–36.Google Scholar
Gavrieli, Y., Sherman, Y., & Ben-Sasson, S.A. (1992). Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. Journal of Cell Biology 119, 493–501.Google Scholar
Gouras, P. & Tanabe, T. (2003). Ultrastructure of adult rd mouse retina. Graefe's Archive for Clinical and Experimental Ophthalmology 241, 410–417.Google Scholar
Guarneri, R., Russo, D., Cascio, C., D'Agostino, S., Galizzi, G., Bigini, P., Mennini, T., & Guarneri, P. (2004). Retinal oxidation, apoptosis and age- and sex-differences in the mnd mutant mouse, a model of neuronal ceroid lipofuscinosis. Brain Research 1014, 209–220.Google Scholar
Hawes, N.L., Smith, R.S., Chang, B., Davisson, M., Heckenlively, J.R., & John, S.W.M. (1999). Mouse fundus photography and angiography: A catalogue of normal and mutant phenotypes. Molecular Vision 5, 22.Google Scholar
Hawes, N.L., Chang, B., Hageman, G.S., Nusinowitz, S., Nishina, P.M., Schneider, B.S., Smith, R.S., Roderick, T.H., & Davisson, M.T. (2000). Retinal degeneration 6 (rd6): A new model for human retinitis punctata albescens. Investigative Ophthalmology and Visual Science 41, 3149–3157.Google Scholar
Heckenlively, J.R., Chang, B., Hawes, N.L., Peng, C., & Roderick, T.H. (1993a). Variable expressivity of rd-3 dependent on strain. Investigative Ophthalmology and Visual Science 34 (ARVO Supplement) 741.Google Scholar
Heckenlively, J.R., Chang, B., Peng, C., Hawes, N.L., & Roderick, T.H. (1993b). Variable expressivity of rd-3 retinal degeneration dependent on background strain. In Retinal Degeneration, ed. Hollyfield, J.G., Anderson, R.E. & LaVail, M.M., pp. 273–280, New York: Plenum Press.
Heckenlively, J.R., Chang, B., Erway, L.C., Peng, C., Hawes, N.L., Hageman, G.S., & Roderick, T.H. (1995). Mouse model for Usher syndrome: Linkage mapping suggests homology to Usher type I reported at human chromosome 11p15. Proceedings of the National Academy of Sciences of the U.S.A. 92, 11100–11104.Google Scholar
Hisatomi, T., Sakamoto, T., Sonoda, K., Tsutsumi, C., Qiao, H., Enaida, H., Yamanaka, I., Kubota, T., Ishibashi, T., Kura, S., Susin, S.A., & Kroemer, G. (2003). Clearance of apoptotic photoreceptors: Elimination of apoptotic debris into the subretinal space and macrophage-mediated phagocytosis via phosphatidylserine receptor and integrin αvβ3. American Journal of Pathology 162, 1869–1879.Google Scholar
Ikeda, S., He, W., Ikeda, A., Naggert, J.K., North, M.A., & Nishina, P.M. (1999). Cell-specific expression of Tubby gene family members (tub, Tulp1, 2, and 3) in the retina. Investigative Ophthalmology and Visual Science 40, 2706–2712.Google Scholar
Lamoreux, M.L., Boissy, R.E., Womack, J.E., & Nordlund, J.J. (1992). The vit gene maps to the mi (microphthalmia) locus of the laboratory mouse. Journal of Heredity 83, 435–439.Google Scholar
LaVail, M.M. (1981). Analysis of neurological mutants with inherited retinal degeneration. Investigative Ophthalmology and Visual Science 21, 638–657.Google Scholar
LaVail, M.M. & Battelle, B.-A. (1975). Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat. Experimental Eye Research 21, 167–192.Google Scholar
LaVail, M.M., Blanks, J.C., & Mullen, R.J. (1982). Retinal degeneration in the pcd cerebellar mutant mouse. I. Light microscopic and autoradiographic analysis. Journal of Comparative Neurology 212, 217–230.Google Scholar
LaVail, M.M., Gorrin, G.M., & Repaci, M.A. (1987). Strain differences in sensitivity to light-induced photoreceptor degeneration in albino mice. Current Eye Research 6, 825–834.Google Scholar
LaVail, M.M., White, M.P., Gorrin, G.M., Yasumura, D., Porrello, K.V., & Mullen, R.J. (1993). Retinal degeneration in the nervous mutant mouse. I. Light microscopic cytopathology and changes in the interphotoreceptor matrix. Journal of Comparative Neurology 333, 168–181.Google Scholar
Lewis, G.P., Guérin, C.J., Anderson, D.H., Matsumoto, B., & Fisher, S.K. (1994). Rapid changes in the expression of glial cell proteins caused by experimental retinal detachment. American Journal of Ophthalmology 118, 368–376.Google Scholar
Lewis, G.P., Linberg, K.A., & Fisher, S.K. (1998). Neurite outgrowth from bipolar and horizontal cells after experimental retinal detachment. Investigative Ophthalmology and Visual Science 39, 424–434.Google Scholar
Linberg, K.A., Fariss, R.N., Heckenlively, J.R., Peng, C., Bowes, C., Farber, D.B., & Fisher, S.K. (1994). Structural changes in the developing retina of the rd-3 mouse. Investigative Ophthalmology and Visual Science 35 (ARVO Supplement) 1610.Google Scholar
Lolley, R.N., Rong, H., & Craft, C.M. (1994). Linkage of photoreceptor degeneration by apoptosis with inherited defect in phototransduction. Investigative Ophthalmology and Visual Science 35, 358–362.Google Scholar
Matsumoto, B. & Hale, I.L. (1993). Preparation of retinas for studying photoreceptors with confocal microscopy. In Methods in Neuroscience, Vol. 15, ed. Hargrave, P.C., pp. 54–71, San Diego, California: Academic Press.
Mehalow, A.K., Kameya, S., Smith, R.S., Hawes, N.L., Denegre, J.M., Young, J.A., Bechtold, L., Haider, N.B., Tepass, U., Heckenlively, J.R., Chang, B., Naggert, J.K., & Nishina, P.M. (2003). CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Human Molecular Genetics 12, 2179–2189.Google Scholar
Messer, A., Plummer, J., Wong, V., & LaVail, M.M. (1993). Retinal degeneration in motor neuron degeneration (mnd) mutant mice. Experimental Eye Research 57, 637–641.Google Scholar
Messer, A., Manley, K., & Plummer, J.A. (1999). An early-onset congenic strain of the motor neuron degeneration (MND) mouse. Molecular Genetics and Metabolism 66, 393–397.Google Scholar
Mullen, R.J. & LaVail, M.M. (1975). Two new types of retinal degeneration in cerebellar mutant mice. Nature 258, 528–530.Google Scholar
Mullen, R.J. & LaVail, M.M. (1976). Inherited retinal dystrophy: Primary defect in pigment epithelium determined with experimental rat chimeras. Science 192, 799–801.Google Scholar
Nusinowitz, S., Peng, C., & Heckenlively, J.R. (1997). Rod and cone electroretinograms (ERGs) in the rd-3 mouse model of retinal degeneration. Investigative Ophthalmology and Visual Science 38, (ARVO Supplement) S886.Google Scholar
Olney, J.W. (1968). An electron microscopic study of synapse formation, receptor outer segment development, and other aspects of developing mouse retina. Investigative Ophthalmology 7, 250–268.Google Scholar
Pang, J., Chang, B., Hawes, N.L., Hurd, R.E., Davisson, M.T., Li, J., Noorwez, S.M., Malhotra, R., McDowell, J.H., Kaushal, S., Hauswirth, W.W., Nusinowitz, S., Thompson, D.A., & Heckenlively, J.R. (2005). Retinal degeneration 12 (rd12): A new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Molecular Vision 11, 152–162.Google Scholar
Portera-Cailliau, C., Sung, C.H., Nathans, J., & Adler, R. (1994). Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proceedings of the National Academy of Sciences of the U.S.A. 91, 974–978.Google Scholar
Roderick, T.H., Chang, B., Hawes, N.L., & Heckenlively, J.P. (1995). New retinal degenerations in the mouse. In Degenerative Diseases of the Retina, ed. Anderson, R.E., LaVail, M.M. & Hollyfield, J.G., pp. 77–85. New York: Plenum Press.
Sanyal, S. & Bal, A.K. (1973). Comparative light and electron microscopic study of retinal histogenesis in normal and rd mutant mice. Zeitschrift für Anatomie und Entwicklungsgeschichte 142, 219–238.Google Scholar
Sanyal, S. & Jansen, H.G. (1981). Absence of receptor outer segments in the retina of rds mutant mice. Neuroscience Letters 21, 23–26.Google Scholar
Sanyal, S., de Ruiter, A., & Hawkins, R.K. (1980). Development and degeneration of retina in rds mutant mice: Light microscopy. Journal of Comparative Neurology 194, 193–207.Google Scholar
Shahinfar, S., Edward, D.P., & Tso, M.O.M. (1991). A pathologic study of photoreceptor cell death in retinal photic injury. Current Eye Research 10, 47–59.Google Scholar
Sidman, R.D., Kosaras, B., & Tang, M. (1996). Pigment epithelial and retinal phenotypes in the vitiligo, mivit, mutant mouse. Investigative Ophthalmology and Visual Science 37, 1097–1115.Google Scholar
Smith, S.B. (1992). C57BL/6J-vit/vit mouse model of retinal degeneration: Light microscopic analysis and evaluation of rhodopsin levels. Experimental Eye Research 55, 903–910.Google Scholar
Smith, S.B. (1995). Evidence of a difference in photoreceptor cell loss in the peripheral versus posterior regions of the vitiligo (C57BL/6J-mivit/mivit) mouse retina. Experimental Eye Research 60, 333–336.Google Scholar
Smith, S.B., Bora, N., McCool, D., Kutty, G., Wong, P., Kutty, R.K., & Wiggert, B. (1995). Photoreceptor cells in the vitiligo mouse die by apoptosis. TRPM-2/clusterin expression is increased in the neural retina and in the retinal pigment epithelium. Investigative Ophthalmology and Visual Science 36, 2193–2201.Google Scholar
Strettoi, E. & Pignatelli, V. (2000). Modifications of retinal neurons in a mouse model of retinitis pigmentosa. Proceedings of the National Academy of Sciences of the U.S.A. 97, 11020–11025.Google Scholar
Strettoi, E., Pignatelli, V., Rossi, C., Porciatti, V., & Falsini, B. (2003). Remodeling of second-order neurons in the retina of rd/rd mutant mice. Vision Research 43, 867–877.Google Scholar
Tso, M.O.M., Zhang, C., Abler, A.S., Chang, C-J., Wong, F., Chang, G.-Q., & Lam, T.T. (1994). Apoptosis leads to photoreceptor degeneration in inherited retinal dystrophy of RCS rats. Investigative Ophthalmology and Visual Science 35, 2693–2699.Google Scholar
Young, R.W. (1984). Cell death during differentiation of the retina in the mouse. Journal of Comparative Neurology 229, 362–373.Google Scholar