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M. Jin, S. Li, S. Nusinowitz, J. Hu, D. Bok, G. H. Travis; Aberrant Trafficking of Retinoids and Cone Degeneration in Mice That Lack IRBP. Invest. Ophthalmol. Vis. Sci. 2008;49(13):156.
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Interphotoreceptor retinoid binding protein (IRBP) is secreted by photoreceptors and represents an abundant component of the interphotoreceptor matrix. IRBP is known to bind visual retinoids and was thought to facilitate the transfer of 11-cis-retinaldehyde (11-cis-RAL) to photoreceptors and all-trans-retinol (all-trans-ROL) to the RPE following a photobleach. However, previous studies on irbp -/- knockout mice showed minimal effects on the trafficking of retinoids. Photoreceptors are known to degenerate in the irbp -/- mice, but the relative rates of rod and cone degeneration are not known. In this study, we re-examined the role of IRBP in the visual cycle and on cone survival.
The irbp -/- mutation was originally generated in 129-strain mice, and then crossed with C57BL/6, which contains the Met450 mutation in the gene for Rpe65-isomerase. We crossed these mice with 129-strain mice to yield irbp -/- mice homozygous for the Leu450 (wild-type allele) of rpe65. We measured the flow of retinoids in retinas and RPE from these mutant and 129 wild-type mice that were exposed to different light conditions. Visual function in these animals was measured by electroretinography (ERG). We measured the content of several photoreceptor and RPE proteins by immunoblotting and immunocytochemistry on retinal sections.
The amount of all-trans-RAL in the retinas of wild-type mice exposed to light at 800 lux for five minutes decreased to approximately 8% after 30 minutes in the dark. In contrast, all-trans-RAL in the irbp -/- retinas only decreased to 20% under the same condition. We observed similar results in isolated retinas. The content of 11-cis-RAL in the RPE of wild-type mice exposed to light at the same condition increased to approximately 13% of total retinoids after 30 minutes in the dark. However, 11-cis-RAL in the RPE of irbp -/- mice only increased to approximately 6% of total retinoids. By ERG analysis we observed a dramatic reduction in cone b-wave amplitudes with much smaller changes in rod b-waves. Immunoblots revealed that several cone-specific proteins were reduced in irbp -/- retinas by immunoblotting, whereas the cognate rod-specific proteins were present at approximately normal levels. Immunocytochemistry showed severe cone degeneration in the irbp -/- retina.
IRBP promotes removal of all-trans-RAL and all-trans-ROL from the neural retina, and 11-cis-RAL from the RPE in vivo. Loss of IRBP results in significantly faster degeneration of cone versus rod photoreceptors. This degeneration may be mediated by the elevated all-trans-RAL or its condensation products.
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