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Gianluca Tosini, Kenkichi Baba, virginie Laurent, David Hicks; Dopamine 2 Receptor Signaling Controls the Daily Burst in Phagocytic Activity by the Retinal Pigment Epithelium.. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Several lines of evidence suggest that dopamine (DA) and its receptors are involved in the regulation of rhythmic retinal pigment epithelium (RPE) functions. For example, inhibition of DA synthesis during the early part of the light phase induced a significant reduction of disk shedding and phagocytosis and mice whose dopaminergic neurons have been destroyed accumulate a large number of residual bodies in the RPE. Previous work from our laboratory has shown that the mouse RPE contains a circadian clock that is synchronized by DA via Dopamine 2 receptor (D2R). In this study we investigated the effects of D2R removal of the daily rhythm of RPE phagocytic activity.
C57/Bl6 and D2R knock-out (KO) in a C57/Bl6 genetic background were used in this study. Phagocytic activity by the RPE was measured by counting the number of phagosomes in the RPE at ZT 23, ZT1 and ZT3 (i.e., before and after light onset) Focal adhesion kinase (FAK) activation was measured by western blotting. Photoreceptor viability was assessed by counting the number of nuclei in the outer nuclear layer (ONL).
The daily burst in phagocytic activity occurring 1-2 hours after light onset was not longer present in D2R KO mice. FAK activation is essential for the engulfment of shed outer segments by the RPE and rhythmic activation of FAK is required for the daily burst of phagocytic activity. C57/Bl6 mice showed a clear increase of FAK-P-Y397/FAK 1 hr. after light onset (One way Anova, P < 0.05) whereas D2R KOs mice did not show any significant increase in the levels of FAK-P-Y397/FAK (One way Anova, P > 0.1). Morphometric analysis of D2R KO mice also indicated a significant reduction in the number of nuclei in the ONL of 10 months old D2R KO (One way Anova P < 0.05). Finally, removal of D2R signaling induced significant changes in the daily pattern of clock and clock controlled genes expression.
Our data indicate that D2R signaling is involved in the timing of the daily burst of phagocytic activity by the RPE. Our results also indicate that the lack of the daily burst in phagocytic activity may affect photoreceptor viability.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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