The Journal of Experimental Medicine
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Published online 13 December 2004 doi:10.1084/jem.20041447
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1539-1545
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Loss of Synchronized Retinal Phagocytosis and Age-related Blindness in Mice Lacking {alpha}vß5 Integrin

Emeline F. Nandrot1, Yoonhee Kim1, Scott E. Brodie1,3, Xiaozhu Huang4, Dean Sheppard4, and Silvia C. Finnemann1,2

1 Margaret M. Dyson Vision Research Institute, Department of Ophthalmology
2 Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10021
3 Department of Ophthalmology, Mount Sinai School of Medicine, New York, NY 10029
4 Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143

Address correspondence to Silvia C. Finnemann, Dyson Vision Research Institute, LC305, Box 233, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Phone: (212) 746-2278; Fax: (212) 746-8444; email: sfinne{at}med.cornell.edu

Daily phagocytosis by the retinal pigment epithelium (RPE) of spent photoreceptor outer segment fragments is critical for vision. In the retina, early morning circadian photoreceptor rod shedding precedes synchronized uptake of shed photoreceptor particles by RPE cells. In vitro, RPE cells use the integrin receptor {alpha}vß5 for particle binding. Here, we tested RPE phagocytosis and retinal function in ß5 integrin–deficient mice, which specifically lack {alpha}vß5 receptors. Retinal photoresponses severely declined with age in ß5–/– mice, whose RPE accumulated autofluorescent storage bodies that are hallmarks of human retinal aging and disease. ß5–/– RPE in culture failed to take up isolated photoreceptor particles. ß5–/– RPE in vivo retained basal uptake levels but lacked the burst of phagocytic activity that followed circadian photoreceptor shedding in wild-type RPE. Rhythmic activation of focal adhesion and Mer tyrosine kinases that mediate wild-type retinal phagocytosis was also completely absent in ß5–/– retina. These results demonstrate an essential role for {alpha}vß5 integrin receptors and their downstream signaling pathways in synchronizing retinal phagocytosis. Furthermore, they identify the ß5–/– integrin mouse strain as a new animal model of age-related retinal dysfunction.

Key Words: circadian rhythm • knockout • photoreceptors • retinal pigment • epithelium • vision

Abbreviations used in this paper: ERG, electroretinogram; FAK, focal adhesion kinase; MerTK, Mer tyrosine kinase, POS, photoreceptor outer segment fragments; RPE, retinal pigment epithelium.


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