Genetic analysis of the circadian system in <i>Drosophila melanogaster</i> and mammals

Stanewsky, Ralf

doi:10.1002/neu.10164

Cited by 205 publications

(160 citation statements)

References 195 publications

(290 reference statements)

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“…In mice, mPeriod's (mPer's) and Chryptochrome's (Cry's) feedback inhibit their own synthesis by inactivating their transcriptional activator CLOCK/BMAL-1 (CLK/BMAL1) (for review, see Gachon et al 2004). In Drosophila, Per and Timless (Tim) inhibit their activator dCLOCK/CYCLE (dCLK/CYC) (for review, see Stanewsky 2003;Hardin 2005). mPER/CRY in mice and PER/TIM in flies are hyperphosphorylated in the course of a circadian period and then degraded.…”

Section: Discussionmentioning

confidence: 99%

“…The rhythms are supported by cell-autonomous circadian clocks, which regulate expression of a large number of genes on the level of transcription (for review, see Roenneberg and Merrow 2003;Stanewsky 2003;Dunlap and Loros 2004;Gachon et al 2004;Iwasaki and Kondo 2004;Salome and McClung 2004;Hardin 2005). Most if not all genes in cyanobacteria and ∼10% of the genes in eukaryotes are transcribed under clock control, generating the potential to modulate thousands of biochemical and physiological parameters in rhythmic fashion (McDonald and Rosbash 2001;Akhtar et al 2002;Duffield et al 2002;Lewis et al 2002;Correa et al 2003;Nowrousian et al 2003;Oishi et al 2003;Nakahira et al 2004).…”

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confidence: 99%

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Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Brunner¹,

Schafmeier²

2006

Genes Dev.

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Circadian clocks are self-sustained oscillators modulating rhythmic transcription of large numbers of genes. Clock-controlled gene expression manifests in circadian rhythmicity of many physiological and behavioral functions. In eukaryotes, expression of core clock components is organized in a network of interconnected positive and negative feedback loops. This network is thought to constitute the pacemaker that generates circadian rhythmicity. The network of interconnected loops is embedded in a supra-net via a large number of interacting factors that affect expression and function of core clock components on transcriptional and post-transcriptional levels. In particular, phosphorylation and dephosphorylation of clock components are critical processes ensuring robust self-sustained circadian rhythmicity and entrainment of clocks to external cues. In cyanobacteria, three clock proteins have the capacity to generate a self-sustained circadian rhythm of autophosphorylation and dephosphorylation independent of transcription and translation. This phosphorylation rhythm regulates the function of these clock components, which then facilitate rhythmic gene transcription, including negative feedback on their own genes. In this article, we briefly present the mechanism of clock function in cyanobacteria. We then discuss in detail the contribution of transcriptional feedback and protein phosphorylation to various functional aspects of the circadian clock of Neurospora crassa.Circadian rhythms are found in numerous light-perceiving organisms including cyanobacteria, algae, fungi, plants, insects, and vertebrates. The rhythms are supported by cell-autonomous circadian clocks, which regulate expression of a large number of genes on the level of transcription (for review, see Transcriptional/translational feedback loops are hallmarks of circadian clocks in all organisms. In eukaryotes, expression of core clock components is organized in a complex network of interconnected positive and negative feedback loops (for review, see Dunlap and Loros 2004;Gachon et al. 2004;Hardin 2005). This network of gene expression is assumed to generate circadian rhythmicity. Elimination of key components of these interconnected loops disrupts many, if not all, rhythmic outputs, depending on the organism. Expression, subcellular localization, assembly, function, and turnover of clock components are crucial for circadian rhythmicity, and thus, the core clock is embedded in a supra-net of cellular machinery regulating various aspects of clock function. Protein phosphorylation and dephosphorylation are important regulatory mechanisms that are critical for self-sustained circadian rhythmicity and entrainment of clocks to external cues. It is unclear to what extent reversible phosphorylations are mechanistically instrumental for generation of rhythmicity in eukaryotic clocks.Recent findings have shown that clock proteins in cyanobacteria generate a self-sustained circadian rhythm of autophosphorylation and dephosphorylation, which is independent of tra...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Brunner¹,

Schafmeier²

2006

Genes Dev.

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“…It is the PER protein and not the mRNA that may regulate gene transcription; for example, at the promoter level by interfering with the other clock protein/transcription factors (Stanewsky, 2003). Thus, the information on the rhythm of PER protein levels as opposed to mRNA levels in a brain region, such as the striatum, appears to be relevant for understanding the putative link between Per expression and cocaine sensitization.…”

Section: Discussionmentioning

confidence: 99%

The Pineal Gland is Critical for Circadian Period1 Expression in the Striatum and for Circadian Cocaine Sensitization in Mice

Akhisaroğlu

Ahmed

et al. 2003

Neuropsychopharmacol

107

106

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Sensitization to psychostimulants can be influenced by circadian rhythms. The pineal gland, the main source of circadian melatonin synthesis, may influence behavioral sensitization to cocaine; mice with normal melatonin rhythms do not get sensitized at night. Clock genes such as Period1 (Per1) show rhythmic region-and strain-dependent expression in the mouse brain, and mice mutant for the Per1 gene lack cocaine sensitization. Here, for the first time we show circadian changes of PER1 protein levels in the mouse striatum, a brain region crucial for the development of locomotor sensitization to cocaine. In male C3H/HeJ mice, we found peak striatal PER1 protein levels during the day; this was preceded by a Per1 mRNA peak 16 h earlier. Pinealectomized mice did not show this circadian pattern. We analyzed circadian cocaine sensitization at times when striatal PER1 protein levels in control mice (naive and sham-pinealectomized) were high and low, respectively. Only mice with circadian changes in striatal Per1 expression showed the night-time absence of cocaine sensitization, whereas pinealectomized mice were without circadian changes in striatal Per1 and were sensitized to cocaine regardless of diurnal rhythm. Our results indicate that both the striatal circadian Per1 expression and diurnal locomotor cocaine sensitization are strongly influenced by pineal products. Since we found evidence for the expression of melatonin receptor mRNA in the striatum, we suggest that further studies on pineal-driven mechanisms will help us better understand the mechanisms of drug abuse and identify novel targets for the prevention and/or treatment of addictions.

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confidence: 99%

“…TIM stabilizes PER, and the PER and TIM proteins cooperate in nuclear entry and retention in key pacemaker cells at night (1). TIM degrades rapidly in response to light, releasing PER to repress per and tim transcription (1). D. melanogaster individuals carrying the null mutation per 01 display arrhythmic locomotor activity under constant darkness (DD), whereas in light-dark (LD) cycles, their locomotor activity is elevated under illumination and reduced in darkness, reflecting the ''masking'' effect of light (2,3).…”

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confidence: 99%

Disruption of Cryptochrome partially restores circadian rhythmicity to the arrhythmic period mutant of Drosophila

Collins

Dissel

Gaten

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The Drosophila melanogaster circadian clock is generated by interlocked feedback loops, and null mutations in core genes such as period and timeless generate behavioral arrhythmicity in constant darkness. In light-dark cycles, the elevation in locomotor activity that usually anticipates the light on or off signals is severely compromised in these mutants. Light transduction pathways mediated by the rhodopsins and the dedicated circadian blue light photoreceptor cryptochrome are also critical in providing the circadian clock with entraining light signals from the environment. The cry b mutation reduces the light sensitivity of the fly's clock, yet locomotor activity rhythms in constant darkness or light-dark cycles are relatively normal, because the rhodopsins compensate for the lack of cryptochrome function. Remarkably, when we combined a period-null mutation with cry b , circadian rhythmicity in locomotor behavior in light-dark cycles, as measured by a number of different criteria, was restored. This effect was significantly reduced in timeless-null mutant backgrounds. Circadian rhythmicity in constant darkness was not restored, and TIM protein did not exhibit oscillations in level or localize to the nuclei of brain neurons known to be essential for circadian locomotor activity. Therefore, we have uncovered residual rhythmicity in the absence of period gene function that may be mediated by a previously undescribed period-independent role for timeless in the Drosophila circadian pacemaker. Although we do not yet have a molecular correlate for these apparently iconoclastic observations, we provide a systems explanation for these results based on differential sensitivities of subsets of circadian pacemaker neurons to light.anticipation ͉ phase shift ͉ oscillator ͉ hourglass ͉ timeless T he PERIOD (PER) and TIMELESS (TIM) proteins are core components of the negative feedback loop that drives circadian oscillations in Drosophila. TIM stabilizes PER, and the PER and TIM proteins cooperate in nuclear entry and retention in key pacemaker cells at night (1). TIM degrades rapidly in response to light, releasing PER to repress per and tim transcription (1). D. melanogaster individuals carrying the null mutation per 01 display arrhythmic locomotor activity under constant darkness (DD), whereas in light-dark (LD) cycles, their locomotor activity is elevated under illumination and reduced in darkness, reflecting the ''masking'' effect of light (2, 3). Another mutation in the gene encoding the blue-light photoreceptor cryptochrome, cry b , gives attenuated light responses in a circadian context (4-7), but normal circadian locomotor behavior in 24-h LD cycles. As part of another study of seasonal behavioral responses to temperature and light effected via changes in per 3Ј splicing, we generated a per 01 ; cry b double mutant (8). We noted that a modest cycle in wild-type per 3Ј splicing in LD cycles at 29°C was exaggerated in per 01 and cry b mutants, yet in the double mutant, the amplitude of the splicing reverted back to ap...

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Genetic analysis of the circadian system in Drosophila melanogaster and mammals

Cited by 205 publications

References 195 publications

Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

Transcriptional and post-transcriptional regulation of the circadian clock of cyanobacteria and Neurospora

The Pineal Gland is Critical for Circadian Period1 Expression in the Striatum and for Circadian Cocaine Sensitization in Mice

Disruption of Cryptochrome partially restores circadian rhythmicity to the arrhythmic period mutant of Drosophila

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