Lack of alphavbeta5 integrin receptor or its ligand MFG-E8: distinct effects on retinal function.
OBJECTIVE
Diurnal phagocytosis of spent photoreceptor outer segment fragments by the retinal pigment epithelium (RPE) is critical for vision. We recently identified an important role for alphavbeta5 integrin receptors and their ligand Milk fat globule-EGF factor 8 (MFG-E8) in RPE phagocytosis.


METHODS
We compared RPE phagocytosis and retinal function between mice deficient in alphavbeta5 integrin receptors and mice deficient in the secreted integrin ligand MFG-E8.


RESULTS
Both beta5-/- and MFG-E8-/- mice exhibit the same phagocytic defect: RPE cells retain basal uptake activity but completely lack the burst of phagocytic activity as well as the rhythmic activation of Mer tyrosine kinase that follow circadian photoreceptor shedding in wild-type RPE. Strikingly, electroretinogram photoresponses decline with age only in beta5 -/- but not in MFG-E8-/- retina.


CONCLUSIONS
These results identify a critical role of alphavbeta5 integrin receptors and their ligand MFG-E8 in synchronizing retinal phagocytosis. Additionally, we show that lack of alphavbeta5 receptors and MFG-E8 ligand have distinct consequences for retinal function. These intriguing results suggest that loss of phagocytic rhythm is not solely responsible for the age-related blindness of beta5-/- mice.
Nandrot
Emeline F
EF
Department of Ophthalmology, Dyson Vision Research Institute, New York, NY 10065, USA.
Finnemann
Silvia C
SC
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000172:deficiency; D016207:Cytokines; D004195:Disease Models, Animal; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008894:Milk Proteins / Q000378:metabolism*; D010857:Pigment Epithelium of Eye / Q000378:metabolism* / Q000648:ultrastructure; D054390:Receptors, CCR2 / Q000172:deficiency; D019707:Receptors, Chemokine / Q000172:deficiency
D000954:Antigens, Surface; D015415:Biomarkers; D000073883:CX3C Chemokine Receptor 1; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D016023:Integrins; D008024:Ligands; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C403414:integrin alphavbeta8