Core circadian clock genes Per1 and Per2 regulate the rhythm in photoreceptor outer segment phagocytosis

Jun 23, 2021FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Core body clock genes Per1 and Per2 control daily rhythm of light-sensing cell renewal

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Abstract

Mice lacking core circadian clock genes Per1 and Per2 show no daily peak in photoreceptor outer segment phagocytosis.

Photoreceptor outer segment phagocytosis peaks approximately one hour after light onset in normal conditions.
Core clock genes Per1 and Per2 are essential for regulating the daily peak of this phagocytic process.
Rhythmic expression of core clock genes was observed in both wild-type and Per1, Per2 double mutant retinas over 24 hours.
No significant changes in gene expression were found in wild-type photoreceptors at different time points leading up to the peak.
Differential gene expression was identified in retinal pigment epithelium at the peak phagocytic time point compared to adjacent times.
A potential gene interaction network that may regulate photoreceptor outer segment phagocytosis in the retinal pigment epithelium includes genes such as Pacsin1 and Camk2b.

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Retinal photoreceptors undergo daily renewal of their distal outer segments, a process indispensable for maintaining retinal health. Photoreceptor outer segment (POS) phagocytosis occurs as a daily peak, roughly about 1 hour after light onset. However, the underlying cellular and molecular mechanisms which initiate this process are still unknown. Here we show that, under constant darkness, mice deficient for core circadian clock genes (Per1 and Per2) lack a daily peak in POS phagocytosis. By qPCR analysis, we found that core clock genes were rhythmic over 24 hours in both WT and Per1, Per2 double mutant whole retinas. More precise transcriptomics analysis of laser capture microdissected WT photoreceptors revealed no differentially expressed genes between time points preceding and during the peak of POS phagocytosis. In contrast, we found that microdissected WT retinal pigment epithelium (RPE) had a number of genes that were differentially expressed at the peak phagocytic time point compared to adjacent ones. We also found a number of differentially expressed genes in Per1, Per2 double mutant RPE compared to WT ones at the peak phagocytic time point. Finally, based on STRING analysis, we found a group of interacting genes that potentially drive POS phagocytosis in the RPE. This potential pathway consists of genes such as: Pacsin1, Syp, Camk2b, and Camk2d among others. Our findings indicate that Per1 and Per2 are necessary clock components for driving POS phagocytosis and suggest that this process is transcriptionally driven by the RPE.

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Core circadian clock genes Per1 and Per2 regulate the rhythm in photoreceptor outer segment phagocytosis

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