ATAXIN-2 Activates PERIOD Translation to Sustain Circadian Rhythms in
            <i>Drosophila</i>

Lim, Chunghun; Allada, Ravi

doi:10.1126/science.1234785

Cited by 127 publications

(147 citation statements)

References 28 publications

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“…Bantam seems to have a predominant role but it might not be unique. The presence of this type of regulation is not surprising given the large amount of reports demonstrating the importance of RNA metabolism for circadian timekeeping 28,41,[56][57][58][59][60] .…”

Section: Discussionmentioning

confidence: 99%

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

et al. 2015

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The transcription factor CLOCK (CLK) is essential for the development and maintenance of circadian rhythms in Drosophila. However, little is known about how CLK levels are controlled. Here we show that Clk mRNA is strongly regulated post-transcriptionally through its 3 0 UTR. Flies expressing Clk transgenes without normal 3 0 UTR exhibit variable CLK-driven transcription and circadian behaviour as well as ectopic expression of CLK-target genes in the brain. In these flies, the number of the key circadian neurons differs stochastically between individuals and within the two hemispheres of the same brain. Moreover, flies carrying Clk transgenes with deletions in the binding sites for the miRNA bantam have stochastic number of pacemaker neurons, suggesting that this miRNA mediates the deterministic expression of CLK. Overall our results demonstrate a key role of Clk post-transcriptional control in stabilizing circadian transcription, which is essential for proper development and maintenance of circadian rhythms in Drosophila.

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Section: Discussionmentioning

confidence: 99%

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

et al. 2015

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“…Similarly, spinocerebellar type 3 ataxic symptoms also appear to show diurnal variations in symptoms (Wilder-Smith et al, 2003), though this seems to interact with a dyskinesia that is also levodopa responsive. The link could be direct with core function in these networks, as the ATX2 (ATAXIN-2) protein, which is implicated in the expression of spinocerebellar ataxia type 2 (or an increased risk of amyotrophic lateral sclerosis and Parkinsonism), is involved in the activation of the rate-limiting circadian clock component PERIOD in Drosophila (Lim and Allada, 2013) and their daily locomotor behavior (Zhang et al, 2013). In terms of circuit mechanisms, Nutt et al (1997) report that circadian fluctuations in motor symptoms are independent of plasma levels of levodopa.…”

Section: Discussionmentioning

confidence: 99%

Diurnal influences on electrophysiological oscillations and coupling in the dorsal striatum and cerebellar cortex of the anesthetized rat

Frederick

Bourget-Murray

Chapman

et al. 2014

Front. Syst. Neurosci.

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Circadian rhythms modulate behavioral processes over a 24 h period through clock gene expression. What is largely unknown is how these molecular influences shape neural activity in different brain areas. The clock gene Per2 is rhythmically expressed in the striatum and the cerebellum and its expression is linked with daily fluctuations in extracellular dopamine levels and D2 receptor activity. Electrophysiologically, dopamine depletion enhances striatal local field potential (LFP) oscillations. We investigated if LFP oscillations and synchrony were influenced by time of day, potentially via dopamine mechanisms. To assess the presence of a diurnal effect, oscillatory power and coherence were examined in the striatum and cerebellum of rats under urethane anesthesia at four different times of day zeitgeber time (ZT1, 7, 13 and 19—indicating number of hours after lights turned on in a 12:12 h light-dark cycle). We also investigated the diurnal response to systemic raclopride, a D2 receptor antagonist. Time of day affected the proportion of LFP oscillations within the 0–3 Hz band and the 3–8 Hz band. In both the striatum and the cerebellum, slow oscillations were strongest at ZT1 and weakest at ZT13. A 3–8 Hz oscillation was present when the slow oscillation was lowest, with peak 3–8 Hz activity occurring at ZT13. Raclopride enhanced the slow oscillations, and had the greatest effect at ZT13. Within the striatum and with the cerebellum, 0–3 Hz coherence was greatest at ZT1, when the slow oscillations were strongest. Coherence was also affected the most by raclopride at ZT13. Our results suggest that neural oscillations in the cerebellum and striatum, and the synchrony between these areas, are modulated by time of day, and that these changes are influenced by dopamine manipulation. This may provide insight into how circadian gene transcription patterns influence network electrophysiology. Future experiments will address how these network alterations are linked with behavior.

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“…Increasing evidence points to the importance of the circadian clock in controlling mRNA translation, including rhythmic activation of cap-dependent translation factors (6, 7, 28-30), and specific RNA binding proteins that control the translation of core clock genes (31)(32)(33)(34)(35). Although the initiation of translation has long been considered to be the primary control step in translation (36), a growing body of evidence points to translation elongation being regulated (37,38), with phosphorylation and reduction in activity of eEF-2 being a central point in this control.…”

Section: Discussionmentioning

confidence: 99%

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

Caster

Castillo

Sachs

et al. 2016

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

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The circadian clock has a profound effect on gene regulation, controlling rhythmic transcript accumulation for up to half of expressed genes in eukaryotes. Evidence also exists for clock control of mRNA translation, but the extent and mechanisms for this regulation are not known. In Neurospora crassa, the circadian clock generates daily rhythms in the activation of conserved mitogen-activated protein kinase (MAPK) pathways when cells are grown in constant conditions, including rhythmic activation of the well-characterized p38 osmosensing (OS) MAPK pathway. Rhythmic phosphorylation of the MAPK OS-2 (P-OS-2) leads to temporal control of downstream targets of OS-2. We show that osmotic stress in N. crassa induced the phosphorylation of a eukaryotic elongation factor-2 (eEF-2) kinase, radiation sensitivity complementing kinase-2 (RCK-2), and that RCK-2 is necessary for high-level phosphorylation of eEF-2, a key regulator of translation elongation. The levels of phosphorylated RCK-2 and phosphorylated eEF-2 cycle in abundance in wild-type cells but not in cells deleted for OS-2 or the core clock component FREQUENCY (FRQ). Translation extracts from cells grown in constant conditions show decreased translational activity in the late subjective morning, coincident with the peak in eEF-2 phosphorylation, and rhythmic translation of glutathione S-transferase (GST-3) from constitutive mRNA levels in vivo is dependent on circadian regulation of eEF-2 activity. In contrast, rhythms in phosphorylated eEF-2 levels are not necessary for rhythms in accumulation of the clock protein FRQ, indicating that clock control of eEF-2 activity promotes rhythmic translation of specific mRNAs.C ircadian rhythms are the outward manifestation of an endogenous clock mechanism common to nearly all eukaryotes. Depending on the organism and tissue, nearly half of an organism's expressed genes are under control of the circadian clock at the level of transcription (1-4). However, mounting evidence indicates a role for the clock in controlling posttranscriptional mechanisms (5), including translation initiation (6, 7), whereas clock control of translation elongation has not been investigated.The driver of circadian rhythms in Neurospora crassa is an autoregulatory molecular feedback loop composed of the negative elements FREQUENCY (FRQ) and FRQ RNA-interacting helicase (FRH), which inhibit the activity of the positive elements WHITE COLLAR-1 (WC-1) and WC-2 (8-11). WC-1 and WC-2 heterodimerize to form the white collar complex (WCC), which activates transcription of frequency (frq) (8,12,13) and activates transcription of a large set of downstream target genes important for overt rhythmicity (2, 14). One gene directly controlled by the WCC is os-4, which encodes the mitogen-activated protein kinase kinase kinase (MAPKKK) in the osmotically sensitive (OS) MAPK pathway (15). Rhythmic transcription of os-4 leads to rhythmic accumulation of the phosphorylated active form of the downstream p38-like mitogen-activated protein kinase (MAPK) OS-2 (16). In Sac...

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ATAXIN-2 Activates PERIOD Translation to Sustain Circadian Rhythms in Drosophila

Cited by 127 publications

References 28 publications

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

Diurnal influences on electrophysiological oscillations and coupling in the dorsal striatum and cerebellar cortex of the anesthetized rat

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

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