Dopamine 2 receptor signaling controls the daily burst in phagocytic activity in the mouse retinal pigment epithelium

Goyal, Varunika; DeVera, Christopher; Laurent, Virginie; Sellers, Jana T; Chrenek, Micah A; Baba, Kenkichi; Iuvone, P. Michael; Tosini, Gianluca

doi:10.1101/789917

Cited by 6 publications

(36 citation statements)

References 31 publications

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“…Interestingly, there were no differences in the total number of phagosomes engulfed in all mouse models used ( Figure 2F, one-way ANOVA, p > 0.1). We have previously reported that activation of dopamine 2 receptor (D2R) signaling is required for the presence of the diurnal phagocytic peak of photoreceptor outer segments (Goyal et al, 2020a). Thus, we decided to investigate whether removal of Bmal1 from the RPE will also affect D2R expression.…”

Section: Loss Of Bmal1 In the Rpe Dramatically Reduces The Daily Peakmentioning

confidence: 99%

“…Whole eyes were processed for phagosome counting as previously described (Goyal et al, 2020a) and labeled with the primary rhodopsin 4D2 antibody (Abcam, ab98887). Briefly, whole eyes were fixed in 4% paraformaldehyde for at least 3 hours and transferred to 30% sucrose (Fisher, S5-500) for cryoprotection.…”

Section: Phagosome Counting Assaymentioning

confidence: 99%

“…RPE flat mount analysis was performed as previously described (Goyal et al, 2020a(Goyal et al, , 2020b. Briefly, each eye following enucleation was placed in Z-fix (Anatech, 170) for 10 minutes at room temperature and then rinsed up to five times with 0.01M phosphate-buffered saline.…”

Section: Rpe Flat Mount Morphology and Autofluorescence Analysismentioning

confidence: 99%

“…A previous study has also reported that in vivo removal of the mouse daily peak in phagocytic activity has a negative consequence on the health of the RPE and photoreceptors during aging (Nandrot et al, 2004), although more recent work suggests that the lack of the peak may not be detrimental for the health of the RPE and photoreceptors (Goyal et al, 2020a;Nandrot and Finnemann, 2008). In our previous study, we also reported that although the daily rhythm in phagocytic activity in the RPE of D2R KO mice is no longer present, clock genes expression in the RPE is not affected by the removal of D2R signaling (Goyal et al, 2020a). Therefore, we inferred that the lack of a negative phenotype was probably due to persistent circadian regulation of RPE function.…”

Section: Introductionmentioning

confidence: 99%

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The Circadian Clock in the Retinal Pigment Epithelium Controls the Diurnal Rhythm of Phagocytic Activity

DeVera

Dixon

Chrenek

et al. 2020

Preprint

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The diurnal peak of phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segments (POS) is under circadian control, and it is believed that this process involves interactions from both the retina and RPE. Previous studies have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE cells. Thereby, the aim of the current study was to determine whether the circadian clock in the retina and or RPE controls the diurnal phagocytic peak of photoreceptor outer segments and whether selective disruption of the circadian clock in the RPE would affect RPE cells function and the viability during aging. To that aim, we first generated and validated an RPE tissue-specific KO of the essential clock gene, Bmal1, and then we determined the daily rhythm in phagocytic activity by the RPE in mice lacking a functional circadian clock in the retina or RPE. Then using electroretinography, spectral domain-optical coherence tomography, and optomotor response measurements of visual function we determined the effect of Bmal1 removal in young (6-month old) and old (18-month old) mice. RPE morphology and lipofuscin accumulation was also determined in young and old mice. Our data show that the circadian clock in the RPE controls the daily diurnal phagocytic peak of POS. Surprisingly, the lack of a functional RPE circadian clock or the diurnal phagocytic peak does not result in any detectable age-related degenerative phenotype in the retina or RPE. Thus, our results demonstrate that the loss of the circadian clock in the RPE or the lack of the daily peak in phagocytosis of POS does not result in deterioration of photoreceptors or the RPE during aging.

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Section: Loss Of Bmal1 In the Rpe Dramatically Reduces The Daily Peakmentioning

confidence: 99%

Section: Phagosome Counting Assaymentioning

confidence: 99%

Section: Rpe Flat Mount Morphology and Autofluorescence Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Circadian Clock in the Retinal Pigment Epithelium Controls the Diurnal Rhythm of Phagocytic Activity

DeVera

Dixon

Chrenek

et al. 2020

Preprint

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“…Intriguingly, approaches promoting POS degradation through lysosomes re-acidification within impaired RPE cells include stimulation of beta-2 adrenergic, A2A adenosine, and D5 dopamine receptors [ 118 ]. This is interesting since adenosine, norepinephrine, and dopamine, which play a role in retinal function and POS phagocytosis [ 118 , 119 , 120 , 121 , 122 ], are known to variously affect mTOR-, AMPK-, and TFEB-related autophagy and also the proteasome system through stimulation of beta-adrenergic, A2A adenosine, and D1/D2-like dopamine receptors [ 123 , 124 , 125 , 126 , 127 , 128 , 129 ]. Since autophagy–lysosomal dysfunction associated with either an increased activity of mTORC1 or decreased activity of AMPK or TFEB does predispose to RPE and photoreceptors degeneration in experimental models [ 36 , 97 , 129 , 130 , 131 , 132 ], it would be worth investigating whether a coupling between alterations of autophagy activity and catecholamine innervation occurs in the frame of AMD.…”

Section: Cell-clearing Systems In the Rpe As The Keys For Retinal mentioning

confidence: 99%

A Re-Appraisal of Pathogenic Mechanisms Bridging Wet and Dry Age-Related Macular Degeneration Leads to Reconsider a Role for Phytochemicals

Pinelli

Biagioni

Limanaqi

et al. 2020

IJMS

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Which pathogenic mechanisms underlie age-related macular degeneration (AMD)? Are they different for dry and wet variants, or do they stem from common metabolic alterations? Where shall we look for altered metabolism? Is it the inner choroid, or is it rather the choroid–retinal border? Again, since cell-clearing pathways are crucial to degrade altered proteins, which metabolic system is likely to be the most implicated, and in which cell type? Here we describe the unique clearing activity of the retinal pigment epithelium (RPE) and the relevant role of its autophagy machinery in removing altered debris, thus centering the RPE in the pathogenesis of AMD. The cell-clearing systems within the RPE may act as a kernel to regulate the redox homeostasis and the traffic of multiple proteins and organelles toward either the choroid border or the outer segments of photoreceptors. This is expected to cope with the polarity of various domains within RPE cells, with each one owning a specific metabolic activity. A defective clearance machinery may trigger unconventional solutions to avoid intracellular substrates’ accumulation through unconventional secretions. These components may be deposited between the RPE and Bruch’s membrane, thus generating the drusen, which remains the classic hallmark of AMD. These deposits may rather represent a witness of an abnormal RPE metabolism than a real pathogenic component. The empowerment of cell clearance, antioxidant, anti-inflammatory, and anti-angiogenic activity of the RPE by specific phytochemicals is here discussed.

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

et al. 2021

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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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Dopamine 2 receptor signaling controls the daily burst in phagocytic activity in the mouse retinal pigment epithelium

Cited by 6 publications

References 31 publications

The Circadian Clock in the Retinal Pigment Epithelium Controls the Diurnal Rhythm of Phagocytic Activity

The Circadian Clock in the Retinal Pigment Epithelium Controls the Diurnal Rhythm of Phagocytic Activity

A Re-Appraisal of Pathogenic Mechanisms Bridging Wet and Dry Age-Related Macular Degeneration Leads to Reconsider a Role for Phytochemicals

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

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