Taken together, all available evidence indicates that αvβ5 integrin at the apical surface of the RPE has important functions in POS phagocytosis as well as in retinal adhesion. These functions may be largely independent of each other since both are defective immediately following the establishment of mature RPE–photoreceptor interactions in the β5 knockout mouse retina. It is possible that αvβ5 receptors at the same plasma membrane domain of the RPE exist in two independent functional pools that mediate retinal adhesion and POS phagocytosis, respectively. Notably, αvβ5 integrin-dependent FAK-MerTK signaling coincides with the daily burst of rod POS phagocytosis but not with the daily peak of retinal adhesion [19, 95]. Thus, the two distinct functions of αvβ5 receptors at the apical surface of the RPE may utilize different downstream signaling pathways to promote two distinct aspects of RPE–photoreceptor interactions.

Significance of Photoreceptor Outer Segment Renewal for Retinal Function

Photoreceptor function strictly depends on efficient RPE phagocytosis of spent OS. Complete failure of RPE cells to engulf POS causes the rapid photoreceptor degeneration in the RCS rat [63, 98, 99]. Furthermore, the continuous nature of outer segment renewal implies that delay in POS removal will gradually cause POS components to accumulate. Indeed, lipofuscin storage bodies containing a complex mix of lipid and protein buildup in human RPE over time as a direct consequence of incomplete POS digestion [100]. Delayed outer segment opsin degradation in transgenic mice causes lipofuscin accumulation and retinal dysfunction with age [101]. Loss of synchronicity of outer segment clearance in β5 integrin null mice is sufficient to promote accumulation of lipofuscin and loss of photoreceptor function with age [95]. Lipofuscin components likely directly decrease RPE function and viability [94, 102]. Finally, there is much evidence that impaired RPE phagocytosis also contributes to human retinal disease, such as retinitis pigmentosa and age-related macular degeneration [103, 104].

PERSPECTIVE

Numerous interactions between RPE and photoreceptor cells take place at all times in the retina. Important physiological functions of these interactions, such as retinal adhesion and POS renewal, occur at the same site and sometimes simultaneously. In addition, RPE–photoreceptor interactions are highly dynamic and differ among retinal regions with the circadian rhythm or with illumination. Although important recent progress has been made, many aspects of these interactions remain poorly understood at the molecular level. This is particularly true with regard to specific interactions of the RPE with photoreceptor cones. Given the enormous significance of cone function for human vision, it is thus imperative to elucidate the molecular mechanisms of renewal and adhesion, specifically of cone photoreceptors, in the mammalian retina in future studies.

ACKNOWLEDGMENTS

We apologize to those colleagues whose work we did not cite due to space restrictions. This work was supported by National Institutes of Health grants EY13295 and EY17173. S.C.F. is the recipient of a William and Mary Greve Special Scholar Award by Research to Prevent Blindness and of an Irma T. Hirschl Career Award.

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