A5011614179- Circadian rhythm and melatonin
- Photoreceptor and optogenetics research
- Light effects on plants
- Genetics, Aging, and Longevity in Model Organisms
- Neurobiology and Insect Physiology Research
- Sleep and Wakefulness Research
- Spaceflight effects on biology
- Plant Molecular Biology Research
- Microtubule and mitosis dynamics
- Genetic and Kidney Cyst Diseases
- Atomic and Subatomic Physics Research
- Neuroendocrine regulation and behavior
- Protist diversity and phylogeny
- Psychological and Temporal Perspectives Research
- Advanced MRI Techniques and Applications
- Retinal Development and Disorders
MRC Laboratory for Molecular Cell Biology
2025
MRC Laboratory of Molecular Biology
2014-2024
Medical Research Council
2013-2024
The Francis Crick Institute
2023
Nuffield Orthopaedic Centre
2018
University of Oxford
2018
University of Bristol
2011
Circadian (~24-hour) rhythms depend on intracellular transcription-translation negative feedback loops (TTFLs). How these self-sustained cellular clocks achieve multicellular integration and thereby direct daily of behavior in animals is largely obscure. The suprachiasmatic nucleus (SCN) the fulcrum this pathway from gene to cell circuit mammals. We describe type-specific, functionally distinct TTFLs neurons astrocytes SCN show that, absence other clocks, cell-autonomous astrocytic TTFL...
We identified a dominant missense mutation in the SCN transcription factor Zfhx3, termed short circuit (Zfhx3(Sci)), which accelerates circadian locomotor rhythms mice. ZFHX3 regulates via direct interaction with predicted AT motifs target genes. The mutant protein has decreased ability to activate consensus vitro. Using RNA sequencing, we found minimal effects on core clock genes Zfhx3(Sci/+) SCN, whereas expression of neuropeptides critical for intercellular signaling was significantly...
Transcriptional-translational feedback loops (TTFLs) are a conserved molecular motif of circadian clocks. The principal clock in mammals is the suprachiasmatic nucleus (SCN) hypothalamus. In SCN neurons, auto-regulatory on core genes Period (Per) and Cryptochrome (Cry) following nuclear entry their protein products basis oscillation [1Shearman L.P. Sriram S. Weaver D.R. Maywood E.S. Chaves I. Zheng B. Kume K. Lee C.C. van der Horst G.T.J. Hastings M.H. Reppert S.M. Interacting mammalian...
The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network neurons, which cell-autonomous molecular feedback loops determine period and amplitude oscillations individual cells. In contrast, circuit-level properties coherence, synchrony, ensemble are determined by intercellular signals embodied wave gene expression that progresses across SCN. How mechanisms interact timekeeping poorly understood. To explore...
Abstract The hypothalamic suprachiasmatic nuclei (SCN) are the principal mammalian circadian timekeeper, co-ordinating organism-wide daily and seasonal rhythms. To achieve this, cell-autonomous timing by ~20,000 SCN cells is welded into a tight circuit-wide ensemble oscillation. This creates essential, network-level emergent properties of precise, high-amplitude oscillation with tightly defined period phase. Although synchronised, regional cell groups exhibit differentially phased activity,...
The suprachiasmatic nucleus (SCN) is the master circadian clock of mammals, generating and transmitting an internal representation environmental time that produced by cell-autonomous transcriptional/post-translational feedback loops (TTFLs) 10,000 neurons 3500 glial cells. Recently, we showed TTFL function in SCN astrocytes alone sufficient to drive timekeeping behavior, raising questions about respective contributions within circuit. We compared their relative roles mouse explants, either...
The mammalian circadian clock exerts control of daily gene expression through cycles DNA binding. Here, we develop a quantitative model how finite pool BMAL1 protein can regulate thousands target sites over time scales. We used imaging to track dynamic changes in endogenous labelled proteins across peripheral tissues and the SCN. determine contribution multiple rhythmic processes coordinating binding, including cycling molecular abundance, binding affinities, repression. find nuclear...
The suprachiasmatic nucleus (SCN) coordinates circadian rhythms that adapt the individual to solar time. SCN pacemaking revolves around feedback loops in which expression of Period ( Per ) and Cryptochrome Cry genes is periodically suppressed by their protein products. Specifically, PER/CRY complexes act at E-box sequences inhibit transactivation CLOCK/BMAL1 heterodimers. To function effectively, these closed intracellular need be synchronized between cells light/dark cycle. For expression,...
The ∼20,000 cells of the suprachiasmatic nucleus (SCN), master circadian clock mammalian brain, coordinate subordinate cellular clocks across organism, driving adaptive daily rhythms physiology and behavior. canonical model for SCN timekeeping pivots around transcriptional/translational feedback loops (TTFL) whereby PERIOD (PER) CRYPTOCHROME (CRY) proteins associate translocate to inhibit their own expression. fundamental individual interactive behaviors PER CRY in environment mechanisms...
The suprachiasmatic nucleus (SCN) of the hypothalamus is principal circadian pacemaker in mammals, coordinating daily metabolic and physiological rhythms with cycle sleep wakefulness. SCN neurons define time via an auto-regulatory feedback loop which activation Period ( Per) Cryptochrome genes periodically suppressed by their own protein products. Casein kinase 1 (CK1) enzymes have a critical role pacemaking because they phosphorylate PER proteins thereby direct proteasomal degradation. In...
Evolutionarily conserved circadian clocks generate 24-hour rhythms in physiology and behaviour that adapt organisms to their daily seasonal environments. In mammals, the suprachiasmatic nucleus (SCN) of hypothalamus is principal co-ordinator cell-autonomous distributed across all major tissues. The importance robust highlighted by experimental epidemiological associations between disruption human diseases. BMAL1 (a bHLH-PAS domain-containing transcription factor) master positive regulator...
Cryptochromes 1 and 2 (CRY1/2) are key components of the negative limb mammalian circadian clock. Like many peripheral tissues, Cry1 -2 expressed in retina, where they thought to play a role regulating rhythmic physiology. However, studies differ consensus as their localization function, CRY1 immunostaining has not been convincingly demonstrated retina. Here we describe expression function mouse retina both sexes. Unexpectedly, show that is throughout all retinal layers, whereas CRY2...
The suprachiasmatic nucleus (SCN) of the hypothalamus is principal clock driving circadian rhythms physiology and behavior that adapt mammals to environmental cycles. Disruption SCN-dependent compromises health, so understanding SCN time keeping will inform management diseases associated with modern lifestyles. a self-sustaining transcriptional/translational delayed feedback loop (TTFL), whereby negative regulators inhibit their own transcription. Formally, viewed as limit-cycle oscillator,...
Abstract Early mammals were nocturnal until the Cretaceous-Paleogene extinction facilitated their rapid expansion into daytime niches. Diurnality subsequently evolved multiple times, independently, but mechanisms facilitating this switch are unknown. We found that physiological daily temperature shifts oppositely affect circadian clock rhythms in versus diurnal mammals. This occurs through a cell-intrinsic signal inverter, mediated by global differences protein phosphorylation, and effected...
Sleep is regulated by circadian and homeostatic processes. Whereas the suprachiasmatic nucleus (SCN) viewed as principal mediator of control, contributions sub-ordinate local clocks distributed across brain are unknown. To test whether SCN interact to regulate sleep, we used intersectional genetics create temporally chimeric CK1ε Tau mice, in which dopamine 1a receptor (Drd1a)-expressing cells, a powerful pacemaking sub-population SCN, had cell-autonomous period 24 h whereas rest intrinsic...
Abstract The biological clock of the suprachiasmatic nucleus (SCN) orchestrates circadian (approximately daily) rhythms behaviour and physiology that underpin health. SCN cell‐autonomous time‐keeping revolves around a transcriptional/translational feedback loop (TTFL) within which PERIOD (PER1,2) CRYPTOCHROME (CRY1,2) proteins heterodimerise suppress trans‐activation their encoding genes ( Per1,2 ; Cry1,2 ). To explore its contribution to time‐keeping, we used adeno‐associated virus–mediated...
Abstract The mammalian circadian clock exerts substantial control of daily gene expression through cycles DNA binding. Understanding mechanisms driving the is hampered by lack quantitative data, without which predictive mathematical models cannot be developed. Here we develop a understanding how finite pool BMAL1 protein can regulate thousands target sites over time scales. We have used fluorescent correlation spectroscopy (FCS) to track dynamic changes in CRISPR-modified fluorophore-tagged...