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Abstract
PURPOSE: To describe the abnormal phenotype in retinal pigment epithelium (RPE) and neural retina of vitiligo mutant mice from embryonic stages to old age. METHODS: Eyes of wild-type controls and congenic vitiligo mutants were examined by light and electron microscopy from embryonic day (E) 12 to 2 years of age. The amount and distribution of pigment in the RPE was studied in wholemounts. RESULTS: Earliest phenotypic expression of mivit is seen in the RPE, which is abnormally multilayered dorsally at E12 to E13, and contains both hyperpigmented and hypopigmented patches. Postnatally, most RPE cells have abnormally short, compact, apical microvilli not containing melanosomes and not interdigitating with rod outer segments (ROS). Rod outer segments begin to degenerate relatively late, at approximately postnatal day (P) 30, and fragments accumulate in the subretinal space; photoreceptor nuclei decrease in number progressively from approximately P60 to P500. Retinal detachment, more prominent than in most other retinal degenerations, begins as ROS break up. Additional unusual events are the appearance of macrophage-like cells in the subretinal space by P21 to P60 and extensive shedding of photoreceptor nuclei across the external limiting membrane and into the subretinal space from approximately P180 to P500. Photoreceptor cell degeneration follows a radial gradient, more severe centrally, and is more advanced superiorly than inferiorly. By 2 years, almost all rod and cone cells are gone, and the residual neural retina is invaded by heavily pigmented cells. CONCLUSIONS: The initial ocular target of the mivit gene is the RPE, which is abnormal for many weeks before photoreceptor cells differentiate and become demonstrably affected. The authors hypothesize that the slowly progressive photoreceptor cell degeneration is secondary to abnormal function of the RPE. This mutation serves to refocus attention on critical influences of the RPE on function and maintenance of photoreceptor cells.