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Originally published In Press as doi:10.1167/iovs.08-3008 on April 30, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:4858-4864.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3008
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Cone Outer Segment Morphology and Cone Function in the Rpe65–/– Nrl–/– Mouse Retina Are Amenable to Retinoid Replacement

Kannan Kunchithapautham,1 Beth Coughlin,1 Rosalie K. Crouch,2 and Bärbel Rohrer1,2

1From the Department of Neurosciences, Division of Research, and the 2Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina.

PURPOSE. RPE65, a major retinal pigment epithelium protein, is essential in generating 11-cis retinal, the chromophore for all opsins. Without chromophore, cone opsins are mislocalized and cones degenerate rapidly (e.g., Rpe65–/– mouse). Function, survival, and correct targeting of opsins is increased in Rpe65–/– cones on supplying 11-cis retinal. Here, we determine the consequences of 11-cis retinal withdrawal and supplementation on cone development in the all-cone Nrl–/– retina.

METHODS. Rpe65–/– Nrl–/–, Nrl–/–, and wild-type mice were examined. Cone structure was analyzed by using TUNEL assay, electron microscopy, and cone-specific antibodies. Cone function was assessed with light-adapted single-flash ERGs.

RESULTS. Rpe65–/–Nrl–/– mice had an increased number of TUNEL-positive photoreceptors during programmed cell death compared with Nrl–/– mice, in addition to accelerated age-related degeneration. Cone function in Rpe65–/–Nrl–/– mice was minimal, and opsins were mislocalized. Treatment with 11-cis retinal restored cone function, promoted outer segment formation, and enabled opsin trafficking to outer segments. Eliminating Rpe65 prevented rosette formation in Nrl–/– retinas; supplementation of Rpe65–/–Nrl–/– mice with 11-cis retinal resulted in their reoccurrence.

CONCLUSIONS. Taken together, function and opsin trafficking in Nrl–/– and wild-type cones are comparable, confirming and extending our findings that cone maturation and outer segment development are dependent on the presence of chromophore. The data on age-related cone death in Rpe65–/–Nrl–/– mice and the reintroduction of rosettes after 11-cis retinal injections confirm that outer segments, which for steric reasons appear to introduce rosettes in an all-cone retina, are essential for cell survival. These results are important for understanding and treating chromophore-related cone dystrophies.






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