Translational Control of Entrainment and Synchrony of the Suprachiasmatic Circadian Clock by mTOR/4E-BP1 Signaling

Cao, Ruifeng; Robinson, Barry; Xu, Hongwei; Gkogkas, Christos G.; Khoutorsky, Arkady; Alain, Tommy; Yanagiya, Akiko; Nevarko, Tatiana; Liu, Andrew C.; Amir, Shimon; Sonenberg, Nahum

doi:10.1016/j.neuron.2013.06.026

Cited by 131 publications

(133 citation statements)

References 71 publications

(108 reference statements)

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“…Moreover, the ERK1/2 MAPK pathway is also involved in regulating circadian rhythms in SCN and plays an important role in the clock-resetting mechanisms of mammalian circadian clock (40,44,45). Interestingly, mTOR activity also exhibits circadian variations in SCN (46) and has been reported to be crucial for regulating protein synthesis by modulating the phosphorylation of 4EBP and mRNAs with 5Ј-TOP motifs (47,48). Our results fit broadly with these studies suggesting that ERK1/2 MAPK and mTOR activity are critical for regulating translation initiation.…”

Section: Discussionsupporting

confidence: 88%

Phosphorylation of Eukaryotic Translation Initiation Factor 4E and Eukaryotic Translation Initiation Factor 4E-binding Protein (4EBP) and Their Upstream Signaling Components Undergo Diurnal Oscillation in the Mouse Hippocampus

Saraf

Luo

Morris

et al. 2014

Journal of Biological Chemistry

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Background: mRNA translation is crucial for formation of long-term memory. Results: Phosphorylation of eIF4E, 4EBPs, rpS6, Akt, mTOR, and ERK1/2 undergoes diurnal oscillation in mouse hippocampus. Conclusion: Diurnal oscillation in markers of mRNA translation initiation is critical for memory consolidation and persistence. Significance: Circadian oscillation in mRNA translation initiation provides a potential mechanism for persistence of long-term memory.

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Section: Discussionsupporting

confidence: 88%

Phosphorylation of Eukaryotic Translation Initiation Factor 4E and Eukaryotic Translation Initiation Factor 4E-binding Protein (4EBP) and Their Upstream Signaling Components Undergo Diurnal Oscillation in the Mouse Hippocampus

Saraf

Luo

Morris

et al. 2014

Journal of Biological Chemistry

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“…Although rhythmic coordination of transcription and mRNA accumulation has been extensively studied during the last decades, rhythmic translation has been described only recently in mammals. Indeed, it has been shown that the TORC1 pathway is rhythmically activated in mouse liver (12,49), hippocampus (50), and SCN (51), influencing in this way rhythmic ribosome biogenesis (12) or light response and circadian behavior (52,53). Moreover, the circadian clock, in coordination with feeding rhythms, seems to play a modulating role in this activation (12,54,55).…”

Section: Translation Efficiency Is Regulated During the Diurnal Cyclementioning

confidence: 99%

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver

Atger

Gobet

Marquis

et al. 2015

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

217

287

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Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5′-Terminal Oligo Pyrimidine tract (5′-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5′-UTR (TISU) motif. The increased translation efficiency of 5′-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.circadian rhythms | ribosome profiling | mRNA translation | 5′-TOP sequences | TISU motifs L iving organisms on Earth are subjected to light-dark cycles caused by rotation of the Earth around the sun. To anticipate these changes, virtually all organisms have acquired a circadian timing system during evolution that allows a better adaptation to their environment. As a consequence, most aspects of their physiology are orchestrated in a rhythmic way by the circadian clock (from the Latin circa diem, meaning "about a day"), an endogenous and autonomous oscillator with a period of around 24 h (1, 2). Not surprisingly, perturbations of this clock in mammals lead to pathologies including psychiatric, metabolic, and vascular disorders (1,3,4). At the organismal scale, the oscillatory clockwork is organized in a hierarchal manner. Within the suprachiasmatic nuclei (SCN) of the hypothalamus, the "master clock" receives light input via the retina and communicates timing signals to "enslave" oscillators in peripheral organs (1, 2). The molecular oscillator consists of interconnected transcriptional and translational feedback loops, in which multiple layers of control, including temporal posttranscriptional and posttranslational regulation, play important roles (5). These additional layers of regulation are largely coordinated by systemic cues originating from circadian clock and/or feeding-coordinated rhythmic metabolism, allowing the adjustment of the molecular clo...

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“…Over the course of the day, transcript levels increase, accompanied by an increase in the levels of the relevant proteins. Circadian regulation of translational efficiency via mTOR and MAPK signaling cascades, converging on phosphorylation of the cap-binding protein eIF4E may facilitate this increase, such that by the end of circadian day nuclear complexes of PER and CRY suppress the activity of CLOCK and BMAL1 (Cao et al 2013). Crystal structures recently revealed that CRY1 binds to a PAS domain within CLOCK and a TAD domain within the carboxyl terminus of BMAL1 to switch off transcriptional activation by CLOCK-BMAL1 .…”

Section: A Short History Of the Mammalian Molecular Clockworkmentioning

confidence: 99%

Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

Herzog

Hermanstyne

Smyllie

et al. 2017

Cold Spring Harb Perspect Biol

204

171

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The suprachiasmatic nucleus (SCN) is the principal circadian clock of the brain, directing daily cycles of behavior and physiology. SCN neurons contain a cell-autonomous transcription-based clockwork but, in turn, circuit-level interactions synchronize the 20,000 or so SCN neurons into a robust and coherent daily timer. Synchronization requires neuropeptide signaling, regulated by a reciprocal interdependence between the molecular clockwork and rhythmic electrical activity, which in turn depends on a daytime Na þ drive and nighttime K þ drag. Recent studies exploiting intersectional genetics have started to identify the pacemaking roles of particular neuronal groups in the SCN. They support the idea that timekeeping involves nonlinear and hierarchical computations that create and incorporate timing information through the interactions between key groups of neurons within the SCN circuit. The field is now poised to elucidate these computations, their underlying cellular mechanisms, and how the SCN clock interacts with subordinate circadian clocks across the brain to determine the timing and efficiency of the sleep -wake cycle, and how perturbations of this coherence contribute to neurological and psychiatric illness.W e wake and sleep each day. Hormones reach peak plasma levels at specified times, for example cortisol peaks in the early morning. These, and many other physiological and behavioral, daily rhythms depend on an internal circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. Prior reviews have provided excellent summaries of research progress in the location and function of this body clock (Weaver 1998). This work focuses on recent advances in our understanding of the genetic basis for cell-autonomous generation of circadian time, and how cells within the SCN synchronize their daily rhythms across the circuit to produce a coherent oscillation in neuronal activity. It is these circuit-level emergent properties of the SCN that ultimately direct daily behaviors such as wake and sleep.

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Translational Control of Entrainment and Synchrony of the Suprachiasmatic Circadian Clock by mTOR/4E-BP1 Signaling

Cited by 131 publications

References 71 publications

Phosphorylation of Eukaryotic Translation Initiation Factor 4E and Eukaryotic Translation Initiation Factor 4E-binding Protein (4EBP) and Their Upstream Signaling Components Undergo Diurnal Oscillation in the Mouse Hippocampus

Phosphorylation of Eukaryotic Translation Initiation Factor 4E and Eukaryotic Translation Initiation Factor 4E-binding Protein (4EBP) and Their Upstream Signaling Components Undergo Diurnal Oscillation in the Mouse Hippocampus

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver

Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms

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