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The Journal of Neuroscience, June 15, 1998, 18(12):4511-4520

Early Onset Photoreceptor Abnormalities Induced by Targeted Disruption of the Interphotoreceptor Retinoid-Binding Protein Gene

Gregory I. Liou¹, Yijian Fei¹, Neal S. Peachey², Suraporn Matragoon¹, Shuanghong Wei³, William S. Blaner³, Youxiang Wang⁴, Chengyu Liu⁴, Max E. Gottesman⁴, and Harris Ripps⁵

¹ Department of Ophthalmology, Medical College of Georgia, Augusta, Georgia 30912, ² Hines Veterans Affairs Hospital, Hines, Illinois 60141, and Department of Neurology, Loyola University Medical Center, Maywood, Illinois 60153, ³ Institute of Human Nutrition and ⁴ Institute of Cancer Research, Columbia University, New York, New York 10032, and ⁵ Department of Ophthalmology and Visual Sciences, University of Illinois, Chicago, Illinois 60612

Vision in all vertebrates is dependent on an exchange of retinoids between the retinal pigment epithelium and the visual photoreceptors. It has been proposed that the interphotoreceptor retinoid-binding protein (IRBP) is essential for this intercellular exchange, and that it serves to prevent the potentially cytotoxic effects of retinoids. Although its precise function in vivo has yet to be defined, the early expression of IRBP suggests that it may also be required for normal photoreceptor development. To further assess the biological role of IRBP, we generated transgenic mice with targeted disruption of the IRBP gene (IRBP/ mice). Specifically, homologous recombination was used to replace the first exon and promoter region of the IRBP gene with a phosphoglycerate kinase-promoted neomycin-resistant gene. Immunocytochemical and Western blot analyses demonstrated the absence of IRBP expression in the IRBP/ mice. As early as postnatal day 11, histological examination of the retinas of IRBP/ mice revealed a loss of photoreceptor nuclei and changes in the structural integrity of the receptor outer segments. At 30 d of age, the photoreceptor abnormalities in IRBP/ mice were more severe, and electroretinographic recordings revealed a marked loss in photic sensitivity. In contrast, no morphological or electrophysiological changes were detected in age-matched heterozygotes. These observations indicate that normal photoreceptor development and function are highly dependent on the early expression of IRBP, and that in the absence of IRBP there is a slowly progressive degeneration of retinal photoreceptors.

Key words: homologous recombination; interphotoreceptor retinoid-binding protein (IRBP); photoreceptor degeneration; retinal development; vitamin A deficiency; Electroretinography (ERG)

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18124511-10$05.00/0

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