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E. Strettoi, V. Pignatelli, C. Rossi, C.L. Cepko; Retinal Organization in the Crx-/- Mouse, a Model of Leber's Congenital Amaurosis . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4514.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Leber Congenital Amaurosis (LCA) is the earliest and most severe form of genetic retinal dystrophy causing blindness in the world. An animal model of LCA was recently created in which the cone-rod homeobox (crx) gene was disrupted using homologous recombination. Crx-/- mice display abnormal development and subsequent degeneration of photoreceptors. We studied the morphology of inner retinal cells in crx -/- mice to evaluate the effects of abnormal photoreceptor development and death upon other retinal neurons. We compared the morphology of retinal cells of crx-/- mice to that of rd/rd mutant mice, in which photoreceptors die as a result of a mutation in the rod-specific phosphodiesterase. Rd/rd mice are a well known model of Retinitis Pigmentosa (RP). The status of inner retinal cells in degenerative retinopathy is important in view of the possibility that photoreceptor transplantation or gene therapy might be used to restore vision in LCA and RP. Methods: Immunocytochemistry with cell type-specific antibodies and confocal microscopy were used to screen the morphology of inner retinal cells in crx -/- and rd/rd mice, aged 10-20 days to several months. Rod and cone bipolar cells, horizontal cells, several types of amacrine and ganglion cells were studied. Single cells were studied by delivering lipophilic dye particles to retinal slices with a gene gun. Results: We found profound morphological alterations in retinal second order neurons in crx -/- animals. Changes include profuse sprouting of horizontal cells' axonal complexes and the progressive retraction of dendrites from bipolar cells. The appearance of bipolar cells after photoreceptor death in crx-/- mice was indistinguishable from bipolar cells of rd/rd mice. In an attempt to prevent dendritic underdevelopment in bipolar cells, overexpression of the anti-apoptotic gene bcl-2 was induced in the inner retina of rd/rd mice by crossing them with transgenics overexpressing the anti-apoptotic gene bcl-2 under the neuron-specific enolase promoter. Double mutants exhibited all the morphological abnormalities of rd/rd mice, including the atrophy of dendritic and axonal arborizations of bipolar cells. Yet, the overexpression of bcl-2 reduced horizontal cell loss observed in the rd/rd central retina at three months of age. Conclusions: It is likely that different genetic mechanisms that cause abnormal photoreceptor development and/or degeneration lead to a common pathway that determines modification in second order neurons.
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