The Logic of Circadian Organization in Drosophila

Dissel, Stephane; Hansen, Celia Napier; Özkaya, Özge; Hemsley, Matthew; Kyriacou, Charalambos P.; Rosato, Ezio

doi:10.1016/j.cub.2014.08.023

Cited by 48 publications

(78 citation statements)

References 37 publications

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“…One possibility is based on the multicellular organization of the circadian neural network driving behavioral rhythms. Although it appears that under normal circumstances the PDF-expressing s-LNvs are the key pacemaker neurons driving free-running behavioral rhythms, recent findings suggest that the circadian neural circuitry in the Drosophila brain is less hierarchical than previously thought and that neurons other than the s-LNvs can make strong contributions to behavioral periodicity (64,65). Within this framework, the S826A/S828A mutations might speed up the clockworks in only a few non-s-LNv cells, an event that would somehow alter the circadian neural hierarchy such that behavioral rhythms would be governed by the faster-running cells, not the s-LNvs.…”

Section: Discussionmentioning

confidence: 95%

Identification of Light-Sensitive Phosphorylation Sites on PERIOD That Regulate the Pace of Circadian Rhythms in Drosophila

Yildirim

Chiu

Edery

2016

Molecular and Cellular Biology

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The main components regulating the pace of circadian (Х24 h) clocks in animals are PERIOD (PER) proteins, transcriptional regulators that undergo daily changes in levels and nuclear accumulation by means of complex multisite phosphorylation programs. In the present study, we investigated the function of two phosphorylation sites, at Ser826 and Ser828, located in a putative nuclear localization signal (NLS) on the Drosophila melanogaster PER protein. These sites are phosphorylated by DOUBLETIME (DBT; Drosophila homolog of CK1␦/), the key circadian kinase regulating the daily changes in PER stability and phosphorylation. Mutant flies in which phosphorylation at Ser826/Ser828 is blocked manifest behavioral rhythms with periods slightly longer than 1 h and with altered temperature compensation properties. Intriguingly, although phosphorylation at these sites does not influence PER stability, timing of nuclear entry, or transcriptional autoinhibition, the phospho-occupancy at Ser826/Ser828 is rapidly stimulated by light and blocked by TIMELESS (TIM), the major photosensitive clock component in Drosophila and a crucial binding partner of PER. Our findings identify the first phosphorylation sites on core clock proteins that are acutely regulated by photic cues and suggest that some phosphosites on PER proteins can modulate the pace of downstream behavioral rhythms without altering central aspects of the clock mechanism.A wide variety of life forms exhibit circadian (ϳ24 h) rhythms in metabolism, physiology, and behavior, which are governed by cellular "clocks" based on the expression of species-or tissuespecific sets of clock genes (reviewed in reference 1). In general, clock mechanisms are biochemical oscillators built on interlocked loops of transcriptional negative feedback and protein degradation, wherein a "master" clock transcription factor drives expression of one or more key repressor proteins that, after a delay, feed back to inhibit the transcription factor until the repressor(s) declines in abundance, enabling another round of gene expression (2). This molecular logic of circadian clocks is usually referred to as transcriptional-translational feedback loops (TTFLs). Studies based on a wide range of model systems indicate that the daily changes in the levels of the key clock feedback repressor(s) are driven by complex temporal phosphorylation programs that dictate the pace of the clock (3-6). In animals, PERIOD (PER) proteins are the central components of the negative arm of the clock mechanism and behave as the primary phosphotimer regulating clock speed (3, 4). A major effect of phosphorylation on regulating the pace of the clock is via evoking temporal changes in the stability of PER proteins, which yields daily cycles in their levels that are inextricably linked to clock progression.Studies of Drosophila melanogaster have been instrumental in our understanding of clock mechanisms in general and mammalian ones in particular. The D. melanogaster intracellular clock mechanism is comprised of interlocked tran...

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Section: Discussionmentioning

confidence: 95%

Identification of Light-Sensitive Phosphorylation Sites on PERIOD That Regulate the Pace of Circadian Rhythms in Drosophila

Yildirim

Chiu

Edery

2016

Molecular and Cellular Biology

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“…Menegazzi et al also confirmed a preliminary observation of Vanin et al (2012), where PER and TIM cycle in the Dorsal Neurons (DNs) in advance of the other neurons, suggesting a faster oscillation in these cells. This has been experimentally supported in the laboratory using a functional assay of the DNs in which these cells' influence on the clock cellular network is amplified, resulting in a shorter behavioral period (Dissel et al, 2014). Finally, while locomotor behavior in the wild appears to be dominated by the temperature cycle, the natural light cycle appears to be the more dominant zeitgeber for the cellular expression of PER and TIM (Menegazzi et al, 2013;Vanin et al, 2012).…”

Section: Introductionmentioning

confidence: 97%

Genetic Analysis of Drosophila Circadian Behavior in Seminatural Conditions

Green

O’Callaghan

Pegoraro

et al. 2015

Methods in Enzymology

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“…Restoring a wild-type copy in the morning neurons of na mutant flies does not restore wild-type rhythmic behavior, while restoring na in the evening neurons does (Lear et al 2005a). Finally, interfering with the neuronal clocks through the overexpression of a dominant-negative CLK mutant in the evening neurons severely weakens behavioral rhythmicity in a light/dark cycle and results in arrhythmic flies in constant dark conditions (Dissel et al 2014). Therefore, the LNds, while retaining some autonomy of their own clock, are responsible for communicating instructions from the s-LNvs (by way of PDF) to downstream targets to regulate rhythmic behavior.…”

Section: The Dorsal Lateral Neurons and The Fifth S-lnvmentioning

confidence: 99%

Coordination between Differentially Regulated Circadian Clocks Generates Rhythmic Behavior

Top

Young

2017

Cold Spring Harb Perspect Biol

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Specialized groups of neurons in the brain are key mediators of circadian rhythms, receiving daily environmental cues and communicating those signals to other tissues in the organism for entrainment and to organize circadian physiology. In Drosophila, the "circadian clock" is housed in seven neuronal clusters, which are defined by their expression of the main circadian proteins, Period, Timeless, Clock, and Cycle. These clusters are distributed across the fly brain and are thereby subject to the respective environments associated with their anatomical locations. While these core components are universally expressed in all neurons of the circadian network, additional regulatory proteins that act on these components are differentially expressed, giving rise to "local clocks" within the network that nonetheless converge to regulate coherent behavioral rhythms. In this review, we describe the communication between the neurons of the circadian network and the molecular differences within neurons of this network. We focus on differences in protein-expression patterns and discuss how such variation can impart functional differences in each local clock. Finally, we summarize our current understanding of how communication within the circadian network intersects with intracellular biochemical mechanisms to ultimately specify behavioral rhythms. We propose that additional efforts are required to identify regulatory mechanisms within each neuronal cluster to understand the molecular basis of circadian behavior. C ircadian rhythms are behavioral and physiological responses that allow anticipation of daily changes in the environment, such as day/ night cycles. Indeed, circadian rhythms are entrained by diurnal oscillations in light, temperature, and food availability, each of which can be considered a "zeitgeber," or "time giver." Such anticipatory behavior of daily events confers adaptive advantages on individuals that organize physiology around planetary rhythms, as well as within a species as a whole, for purposes of mating, cooperation, protection, etc. In a sense, rhythmic anticipation can be thought of as a primitive mechanism of planning and cognition.The circadian clock, consisting of transcriptional negative feedback loops, underlies the regulation of a ∼24-h behavioral rhythm. The molecular architecture of this feedback loop is conserved across the majority of multicellular organisms. In animals, the "master clock" is housed in specialized pacemaker neurons in the brain that coordinate various "peripheral clocks" throughout the organism to regulate daily physiological and behavioral changes.

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The Logic of Circadian Organization in Drosophila

Cited by 48 publications

References 37 publications

Identification of Light-Sensitive Phosphorylation Sites on PERIOD That Regulate the Pace of Circadian Rhythms in Drosophila

Identification of Light-Sensitive Phosphorylation Sites on PERIOD That Regulate the Pace of Circadian Rhythms in Drosophila

Genetic Analysis of Drosophila Circadian Behavior in Seminatural Conditions

Coordination between Differentially Regulated Circadian Clocks Generates Rhythmic Behavior

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