Suprachiasmatic Nucleus: Cell Autonomy and Network Properties

Welsh, David K.; Takahashi, Joseph S.; Kay, Steve A.

doi:10.1146/annurev-physiol-021909-135919

Cited by 1,064 publications

(1,015 citation statements)

References 213 publications

(314 reference statements)

Supporting

Mentioning

986

Contrasting

Unclassified

Order By: Relevance

“…Through a transcriptional mechanism, the clock controls many important biological pathways, such as metabolism, inflammation, and sleep-wake cycles. [1][2][3] REV-ERBα is a nuclear receptor that has been demonstrated to, upon activation by heme, form a complex with co-factors that represses the transcription of target genes. 4,5 REV-ERBα is at the heart of the circadian clock and is a mechanism by which the circadian clock gates inflammatory response and controls the metabolic state of the organism.…”

Section: Introductionmentioning

confidence: 99%

Optimized Chemical Probes for REV-ERBα

et al. 2013

View full text Add to dashboard Cite

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either IV or oral dosing.

show abstract

Section: Introductionmentioning

confidence: 99%

Optimized Chemical Probes for REV-ERBα

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The second and probably more important difference between the SCN and peripheral organs concerns the communication of phase information between individual cells. In the SCN, the cellular oscillators are coupled through neuronal and paracrine signals, and this establishes phase coherence in the SCN (Welsh et al 2010). Even in cultured brain sections, SCN neurons maintain the same phase for days to weeks.…”

mentioning

confidence: 99%

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

Saini

Suter²,

Liani³

et al. 2011

Cold Spring Harbor Symposia on Quantitative Biology

View full text Add to dashboard Cite

Mammalian physiology has to adapt to daily alternating periods during which animals either forage and feed or sleep and fast. The adaptation of physiology to these oscillations is controlled by a circadian timekeeping system, in which a master pacemaker in the suprachiasmatic nucleus (SCN) synchronizes slave clocks in peripheral organs. Because the temporal coordination of metabolism is a major purpose of clocks in many tissues, it is important that metabolic and circadian cycles are tightly coordinated. Recent studies have revealed a multitude of signaling components that possibly link metabolism to circadian gene expression. Owing to this redundancy, the implication of any single signaling pathway in the synchronization of peripheral oscillators cannot be assessed by determining the steady-state phase, but instead requires the monitoring of phase-shifting kinetics at a high temporal resolution.

show abstract

“…Cell autonomous circadian pacemakers drive these rhythms and synchronize them each day to environmental cues. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus contains the central pacemaker that coordinates the local circadian clocks present in tissues throughout the body (3,4). The molecular clock mechanism within individual cells is composed of transcriptional/translational feedback loops and posttranslational processes (1,5).…”

mentioning

confidence: 99%

Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

Shimomura¹,

Lowrey

Vitaterna³

et al. 2010

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

Self Cite

View full text Add to dashboard Cite

Most laboratory mouse strains including C57BL/6J do not produce detectable levels of pineal melatonin owing to deficits in enzymatic activity of arylalkylamine N-acetyltransferase (AANAT) and Nacetylserotonin O-methyl transferase (ASMT), two enzymes necessary for melatonin biosynthesis. Here we report that alleles segregating at these two loci in C3H/HeJ mice, an inbred strain producing melatonin, suppress the circadian period-lengthening effect of the Clock mutation. Through a functional mapping approach, we localize mouse Asmt to chromosome X and show that it, and the Aanat locus on chromosome 11, are significantly associated with pineal melatonin levels. Treatment of suprachiasmatic nucleus (SCN) explant cultures from Period2 Luciferase (Per2 Luc ) Clock/+ reporter mice with melatonin, or the melatonin agonist, ramelteon, phenocopies the genetic suppression of the Clock mutant phenotype observed in living animals. These results demonstrate that melatonin suppresses the Clock/+ mutant phenotype and interacts with Clock to affect the mammalian circadian system.C ircadian (from the Latin, meaning about a day) rhythms of biochemistry and physiology are innate to virtually all life forms (1, 2). Cell autonomous circadian pacemakers drive these rhythms and synchronize them each day to environmental cues. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus contains the central pacemaker that coordinates the local circadian clocks present in tissues throughout the body (3, 4). The molecular clock mechanism within individual cells is composed of transcriptional/translational feedback loops and posttranslational processes (1, 5). The bHLH-PAS transcription factors CLOCK and BMAL1 form the primary loop as they activate transcription of the Period (Per1 and Per2) and Cryptochrome (Cry1 and Cry2) genes (1, 6). The PER and CRY proteins subsequently feed back to abrogate their own transcription by directly inhibiting the CLOCK:BMAL1 complex. A second feedback loop stabilizes the primary loop and is composed of REV-ERBα and RORa, two retinoic acid-related orphan receptors, which repress and activate, respectively, transcription of Bmal1. Whereas approximately a dozen genes involved in this timekeeping system have been identified in mammals, it is clear that other, as-yet unknown genes regulate key properties of circadian rhythms (7,8).The SCN imparts daily entraining signals to circadian clocks in cells of peripheral tissues via neural connections and humoral factors (9, 10). One well-characterized circadian rhythm synchronized by the SCN is the synthesis and release at night of the lipophilic pineal hormone melatonin (11). Light information reaches the mammalian pineal gland through a multisynaptic pathway that begins with intrinsically photosensitive melanopsin-containing retinal ganglion cells, which project to the SCN via the retinohypothalamic tract, and ultimately terminates at sympathetic afferents of the pineal gland (12, 13). Lesions of the SCN abolish the melatonin circadian rhythm (14). Two high-affi...

show abstract

Suprachiasmatic Nucleus: Cell Autonomy and Network Properties

Cited by 1,064 publications

References 213 publications

Optimized Chemical Probes for REV-ERBα

Optimized Chemical Probes for REV-ERBα

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway

Contact Info

Product

Resources

About