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A local neuronal clock regulates retinal angiogenesis and neovascularization

ABSTRACT: Emerging evidence suggests a link between the circadian clock and retinopathies though the causality has not been established. Circadian clocks in the mammalian retina regulate a diverse range of retinal functions that allow the retina to adapt to the light-dark cycle. We report that clock genes are expressed in the embryonic retina, and the embryonic retina requires light cues to maintain robust circadian expression of the core clock gene, Bmal1. Deletion of Bmal1 and Per2 from the retinal neurons results in retinal angiogenic defects similar to when animals are maintained under constant light conditions. Using two different models to assess pathological neovascularization, we show that neuronal Bmal1 deletion reduces neovascularization with reduced vascular leakage, suggesting that a dysregulated circadian clock primarily drives neovascularization. Chromatin immunoprecipitation sequencing analysis suggests that semaphorin signaling is the dominant pathway regulated by Bmal1. Our data indicate that therapeutic silencing of the retinal clock could be a common approach for the treatment of certain retinopathies like diabetic retinopathy and retinopathy of prematurity.

ORGANISM(S): Mus musculus

PROVIDER: GSE207271 | GEO | 2022/07/01

REPOSITORIES: GEO

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Project description:Retinal function changes dramatically from day to night. Yet, clinical diagnosis, treatments, and experimental sampling occur during the day, leaving a significant gap in our understanding of the pathobiology occurring at night. While there is evidence that diabetes disrupts the circadian system that optimizes our physiology to the environmental light/dark cycle, the impact of such disruption is not well understood. This study investigates whether diabetes affects the retina's daily rhythm of gene expression to understand the pathobiology of diabetic retinopathy, a common complication of diabetes. Control and hyperglycemic littermate mice (Ins2Akita/J) were kept under a standard 12h:12h light/dark cycle until four months of age. Bulk mRNA sequencing was conducted in retinas collected every 4 hours throughout the 24 hr light/dark cycle. Computational approaches were used to detect rhythmicity, predict acrophase, identify differential rhythmic patterns, analyze phase set enrichment, and predict upstream regulators. The retinal transcriptome exhibited a tightly regulated rhythmic expression with a clear 12-hr axis of transcriptional rush, peaking at midday and midnight. The functions of day-peaking genes were enriched for DNA repair, RNA splicing, and ribosomal protein synthesis, whereas night-peaking genes were enriched for metabolic processes and growth factor signaling. Although the 12-hr transcriptional axis is retained in the diabetic retina, it was phase advanced by approximately 1-3 hours with a wider distribution. Upstream regulator analysis for the genes that showed phase shifts identified oxygen sensing mechanisms and HIF1alpha as regulators, but not the circadian clock, which remained in phase to the light/dark cycle. We propose a model in which early in diabetes, the diabetic retina experiences a ‘jet lag’ caused by the entrained circadian clock and its output being in one phase and metabolic pathways related to neuronal dysfunction and hypoxia driving advancement of gene expression to a different phase. Further studies are now required to evaluate the chronic implications of such internal jet lag for development of diabetic retinopathy.

Project description:We extend the study of a computational model recently proposed for the mammalian circadian clock (Proc. Natl Acad. Sci. USA 100 (2003) 7051). The model, based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, and Clock genes, can give rise to sustained circadian oscillations in conditions of continuous darkness. These limit cycle oscillations correspond to circadian rhythms autonomously generated by suprachiasmatic nuclei and by some peripheral tissues. By using different sets of parameter values producing circadian oscillations, we compare the effect of the various parameters and show that both the occurrence and the period of the oscillations are generally most sensitive to parameters related to synthesis or degradation of Bmal1 mRNA and BMAL1 protein. The mechanism of circadian oscillations relies on the formation of an inactive complex between PER and CRY and the activators CLOCK and BMAL1 that enhance Per and Cry expression. Bifurcation diagrams and computer simulations nevertheless indicate the possible existence of a second source of oscillatory behavior. Thus, sustained oscillations might arise from the sole negative autoregulation of Bmal1 expression. This second oscillatory mechanism may not be functional in physiological conditions, and its period need not necessarily be circadian. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark (LD) cycles. Long-term suppression of circadian oscillations by a single light pulse can occur in the model when a stable steady state coexists with a stable limit cycle. The phase of the oscillations upon entrainment in LD critically depends on the parameters that govern the level of CRY protein. Small changes in the parameters governing CRY levels can shift the peak in Per mRNA from the L to the D phase, or can prevent entrainment. The results are discussed in relation to physiological disorders of the sleep-wake cycle linked to perturbations of the human circadian clock, such as the familial advanced sleep phase syndrome or the non-24h sleep-wake syndrome.

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A local neuronal clock regulates retinal angiogenesis and neovascularization

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