Reciprocal Relationship Between Calcium Signaling and Circadian Clocks: Implications for Calcium Homeostasis, Clock Function, and Therapeutics

Cavieres-Lepe, Javier; Ewer, John

doi:10.3389/fnmol.2021.666673

Cited by 21 publications

(13 citation statements)

References 113 publications

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“…Our data show a significant and substantial decrease in transcript levels of multiple phototransduction genes, and we propose that the cumulative decrease in expression of their corresponding proteins causes the light-dependent retinal degeneration in flies expressing Clk DN . However, because disrupting Clk:Cyc activity in photoreceptors had widespread effects on gene expression and chromatin accessibility, we cannot exclude the possibility that other pathways such as autophagy [77], Ca 2+ signaling [78] and phosphoinositide metabolism [79] also contribute to the onset of light-dependent retinal degeneration.…”

Section: Plos Geneticsmentioning

confidence: 99%

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

et al. 2022

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The aging eye experiences physiological changes that include decreased visual function and increased risk of retinal degeneration. Although there are transcriptomic signatures in the aging retina that correlate with these physiological changes, the gene regulatory mechanisms that contribute to cellular homeostasis during aging remain to be determined. Here, we integrated ATAC-seq and RNA-seq data to identify 57 transcription factors that showed differential activity in aging Drosophila photoreceptors. These 57 age-regulated transcription factors include two circadian regulators, Clock and Cycle, that showed sustained increased activity during aging. When we disrupted the Clock:Cycle complex by expressing a dominant negative version of Clock (ClkDN) in adult photoreceptors, we observed changes in expression of 15–20% of genes including key components of the phototransduction machinery and many eye-specific transcription factors. Using ATAC-seq, we showed that expression of ClkDN in photoreceptors leads to changes in activity of 37 transcription factors and causes a progressive decrease in global levels of chromatin accessibility in photoreceptors. Supporting a key role for Clock-dependent transcription in the eye, expression of ClkDN in photoreceptors also induced light-dependent retinal degeneration and increased oxidative stress, independent of light exposure. Together, our data suggests that the circadian regulators Clock and Cycle act as neuroprotective factors in the aging eye by directing gene regulatory networks that maintain expression of the phototransduction machinery and counteract oxidative stress.

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Section: Plos Geneticsmentioning

confidence: 99%

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

et al. 2022

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“…In humans, MICU3 is a brain-specific isoform of the mitochondrial calcium uniporter subunit particularly expressed in astrocytes, thus suggesting that a dysregulated mitochondrial calcium uptake in astrocytes contributes to PD progression [ 42 ]. It is not surprising, though, that knockdown of a gene like MICU3 results in altered behavioural locomotion, as calcium signalling is central for regulating circadian behaviour [ 43 ]. CtsB1 and CG33181 knockdown lines displayed normal climbing ability at day 5 and exacerbate climbing ability at days 10 and 15 ( Figure 3 and Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Functionally Validating Evolutionary Conserved Risk Genes for Parkinson’s Disease in Drosophila melanogaster

Baisgaard

Koldby

Kristensen

et al. 2023

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Parkinson’s disease (PD) is a heterogeneous and complex neurodegenerative disorder and large-scale genetic studies have identified >130 genes associated with PD. Although genomic studies have been decisive for our understanding of the genetic contributions underlying PD, these associations remain as statistical associations. Lack of functional validation limits the biological interpretation; however, it is labour extensive, expensive, and time consuming. Therefore, the ideal biological system for functionally validating genetic findings must be simple. The study aim was to assess systematically evolutionary conserved PD-associated genes using Drosophila melanogaster. From a literature review, a total of 136 genes have found to be associated with PD in GWAS studies, of which 11 are strongly evolutionary conserved between Homo sapiens and D. melanogaster. By ubiquitous gene expression knockdown of the PD-genes in D. melanogaster, the flies’ escape response was investigated by assessing their negative geotaxis response, a phenotype that has previously been used to investigate PD in D. melanogaster. Gene expression knockdown was successful in 9/11 lines, and phenotypic consequences were observed in 8/9 lines. The results provide evidence that genetically modifying expression levels of PD genes in D. melanogaster caused reduced climbing ability of the flies, potentially supporting their role in dysfunctional locomotion, a hallmark of PD.

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“…Interestingly, UCP1 gene expression is regulated by the clock gene Reverbα and, therefore, exhibits circadian rhythmicity in BAT ( 23 ). In addition, many genes encoding proteins involved in Ca 2+ signaling are circadianly expressed in the skeletal muscle, and at least a subset of them, including the SERCA gene, may be regulated by the core clock component CLOCK-BMAL1 ( 24 , 25 ). Furthermore, we have shown that mice with brown adipocyte-specific Bmal1 KO show reduced thermogenesis despite the elevated expression of UCP1, probably due to impaired fatty acid utilization in BAT ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Sustained effect of habitual feeding time on daily rhythm of core body temperature in mice

et al. 2022

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Background and aimCircadian clocks in most peripheral tissues are entrained mainly by feeding. Therefore, this study aimed to investigate whether the daily rhythm of core body temperature (CBT), including the effect of diet-induced thermogenesis, varies according to habitual feeding time.MethodsWild-type and uncoupling protein 1 (UCP1) knockout mice were fed only during the first 4 h (Breakfast group) or the last 4 h of the dark period (Dinner group) for 17 days. On day 18, both groups were fed twice for 2 h, at the same starting times. Locomotor activity and CBT were measured continuously during the experiment.ResultsOn day 18, CBT increased at the beginning of each feeding period, regardless of the group and strain. However, the CBT increase induced by the first meal decreased sharply in the Breakfast group and mildly in the Dinner group; the opposite was observed after the second meal. In UCP1 knockout, but not wild-type, mice, the total amount of CBT was significantly lower in the Dinner group than in the Breakfast group. These effects were mostly independent of the locomotor activity and food intake.ConclusionThese results reveal that the effect of habitual feeding time on the daily rhythm of CBT is sustained at least until the following day. These effects may be mediated by both UCP1-dependent and -independent mechanisms.

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Reciprocal Relationship Between Calcium Signaling and Circadian Clocks: Implications for Calcium Homeostasis, Clock Function, and Therapeutics

Cited by 21 publications

References 113 publications

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

The Clock:Cycle complex is a major transcriptional regulator of Drosophila photoreceptors that protects the eye from retinal degeneration and oxidative stress

Functionally Validating Evolutionary Conserved Risk Genes for Parkinson’s Disease in Drosophila melanogaster

Sustained effect of habitual feeding time on daily rhythm of core body temperature in mice

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