Circadian regulation of the retinal pigment epithelium–photoreceptor complex

Photoreceptors lie in close contact with the retinal pigment epithelium (RPE) forming a single multi-functional unit central to vision and retina survival. Little is known about the physiological functions regulated by the circadian clock in the RPE – photoreceptor complex. The rhythmic phagocytosis of photoreceptor outer segments (POS) is essential for retinal health. In this thesis, we found no rhythm in phagocytosis of POS in mice carrying a double clock gene Per1, Per2 mutation. There were no obvious transcriptional links between the circadian clock and POS phagocytosis in wild-type mouse photoreceptors. We found that most of the phagocytosis machinery is rhythmic on a transcriptional, protein and functional level in ARPE-19 (RPE) cells. This machinery is modulated by POS and the clock gene REV-ERBα. We found that other aspects of RPE physiology also oscillate. Our results suggested that RPE-mediated ion transport is rhythmic via the sodium-potassium-chloride cotransporter NKCC1. We also found a rhythm in RPE-mediated transport of lactate via the monocarboxylate transporter SLC16A1 (MCT1). In contrast, we found no evidence of rhythmic glucose transport by the RPE. This thesis sheds some light on the regulation of POS phagocytosis and expands the repertoire of circadian clock-regulated physiology of the RPE-photoreceptor complex.