Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 200, Issue 12, Pages 1539-1545Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20041447
Keywords
circadian rhythm; knockout; photoreceptors; retinal pigment epithelium; vision
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Funding
- NEI NIH HHS [R01 EY013295, R03 EY014184, EY13295, EY14184] Funding Source: Medline
- NHLBI NIH HHS [HL53949, R01 HL064353, R01 HL053949, HL64353, R37 HL053949] Funding Source: Medline
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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 alphanubeta5 for particle binding. Here, we tested RPE phagocytosis and retinal function in beta5 integrin-deficient mice, which specifically lack alphanubeta5 receptors. Retinal photoresponses severely declined with age in beta5(-/-) mice, whose RPE accumulated autofluorescent storage bodies that are hallmarks of human retinal aging and disease. beta5(-/-) RPE in culture failed to take up isolated photoreceptor particles. beta(5-/-) 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 beta5(-/-) retina. These results demonstrate an essential role for alphanubeta5 integrin receptors and their downstream signaling pathways in synchronizing retinal phagocytosis. Furthermore, they identify the beta5(-/-) integrin mouse strain as a new animal model of age-related retinal dysfunction.
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