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  1. Article ; Online: The Mammalian Circadian Timing System and the Suprachiasmatic Nucleus as Its Pacemaker

    Michael H. Hastings / Elizabeth S. Maywood / Marco Brancaccio

    Biology, Vol 8, Iss 1, p

    2019  Volume 13

    Abstract: The past twenty years have witnessed the most remarkable breakthroughs in our understanding of the molecular and cellular mechanisms that underpin circadian (approximately one day) time-keeping. Across model organisms in diverse taxa: cyanobacteria ( ... ...

    Abstract The past twenty years have witnessed the most remarkable breakthroughs in our understanding of the molecular and cellular mechanisms that underpin circadian (approximately one day) time-keeping. Across model organisms in diverse taxa: cyanobacteria (Synechococcus), fungi (Neurospora), higher plants (Arabidopsis), insects (Drosophila) and mammals (mouse and humans), a common mechanistic motif of delayed negative feedback has emerged as the Deus ex machina for the cellular definition of ca. 24 h cycles. This review will consider, briefly, comparative circadian clock biology and will then focus on the mammalian circadian system, considering its molecular genetic basis, the properties of the suprachiasmatic nucleus (SCN) as the principal circadian clock in mammals and its role in synchronising a distributed peripheral circadian clock network. Finally, it will consider new directions in analysing the cell-autonomous and circuit-level SCN clockwork and will highlight the surprising discovery of a central role for SCN astrocytes as well as SCN neurons in controlling circadian behaviour.
    Keywords astrocytes ; entrainment ; photoperiod ; suprachiasmatic ; period ; cryptochrome ; sleep ; clock ; Bmal1 ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Vasoactive intestinal peptide controls the suprachiasmatic circadian clock network via ERK1/2 and DUSP4 signalling

    Ryan Hamnett / Priya Crosby / Johanna E. Chesham / Michael H. Hastings

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 17

    Abstract: The suprachiasmatic nucleus (SCN) synchronises daily rhythms of behaviour and physiology to the light-dark cycle. Vasoactive intestinal peptide (VIP) is important for mediating SCN entrainment; however, the underlying mechanisms are incompletely ... ...

    Abstract The suprachiasmatic nucleus (SCN) synchronises daily rhythms of behaviour and physiology to the light-dark cycle. Vasoactive intestinal peptide (VIP) is important for mediating SCN entrainment; however, the underlying mechanisms are incompletely understood. Here, the authors show that the effects of VIP on the SCN are mediated by ERK1/2 and DUSP4.
    Keywords Science ; Q
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Vasoactive intestinal peptide controls the suprachiasmatic circadian clock network via ERK1/2 and DUSP4 signalling

    Ryan Hamnett / Priya Crosby / Johanna E. Chesham / Michael H. Hastings

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 17

    Abstract: The suprachiasmatic nucleus (SCN) synchronises daily rhythms of behaviour and physiology to the light-dark cycle. Vasoactive intestinal peptide (VIP) is important for mediating SCN entrainment; however, the underlying mechanisms are incompletely ... ...

    Abstract The suprachiasmatic nucleus (SCN) synchronises daily rhythms of behaviour and physiology to the light-dark cycle. Vasoactive intestinal peptide (VIP) is important for mediating SCN entrainment; however, the underlying mechanisms are incompletely understood. Here, the authors show that the effects of VIP on the SCN are mediated by ERK1/2 and DUSP4.
    Keywords Science ; Q
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock

    Alex A Koch / James S Bagnall / Nicola J Smyllie / Nicola Begley / Antony D Adamson / Jennifer L Fribourgh / David G Spiller / Qing-Jun Meng / Carrie L Partch / Korbinian Strimmer / Thomas A House / Michael H Hastings / Andrew SI Loudon

    eLife, Vol

    2022  Volume 11

    Abstract: The mammalian circadian clock exerts control of daily gene expression through cycles of DNA binding. Here, we develop a quantitative model of how a finite pool of BMAL1 protein can regulate thousands of target sites over daily time scales. We used ... ...

    Abstract The mammalian circadian clock exerts control of daily gene expression through cycles of DNA binding. Here, we develop a quantitative model of how a finite pool of BMAL1 protein can regulate thousands of target sites over daily time scales. We used quantitative imaging to track dynamic changes in endogenous labelled proteins across peripheral tissues and the SCN. We determine the contribution of multiple rhythmic processes coordinating BMAL1 DNA binding, including cycling molecular abundance, binding affinities, and repression. We find nuclear BMAL1 concentration determines corresponding CLOCK through heterodimerisation and define a DNA residence time of this complex. Repression of CLOCK:BMAL1 is achieved through rhythmic changes to BMAL1:CRY1 association and high-affinity interactions between PER2:CRY1 which mediates CLOCK:BMAL1 displacement from DNA. Finally, stochastic modelling reveals a dual role for PER:CRY complexes in which increasing concentrations of PER2:CRY1 promotes removal of BMAL1:CLOCK from genes consequently enhancing ability to move to new target sites.
    Keywords circadian ; live-cell imaging ; FRAP ; single cell quantification ; modelling ; DNA binding ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Zfhx3-mediated genetic ablation of the SCN abolishes light entrainable circadian activity while sparing food anticipatory activity

    Ashleigh G. Wilcox / R. Sonia Bains / Debbie Williams / Elizabeth Joynson / Lucie Vizor / Peter L. Oliver / Elizabeth S. Maywood / Michael H. Hastings / Gareth Banks / Patrick M. Nolan

    iScience, Vol 24, Iss 10, Pp 103142- (2021)

    2021  

    Abstract: Summary: Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been ...

    Abstract Summary: Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been genetically ablated by conditional deletion of the transcription factor Zfhx3 in the developing hypothalamus. Mutants were arrhythmic over the light-dark cycle and in constant darkness. Moreover, rhythms of metabolic parameters were ablated in vivo although molecular oscillations in the liver maintained some rhythmicity. Despite disruptions to SCN cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity although activity levels in mutants were altered. This work highlights a critical role for Zfhx3 in the development of a functional SCN, while its genetic ablation further defines the contribution of SCN circuitry in orchestrating physiological and behavioral responses to environmental signals.
    Keywords Biological sciences ; Physiology ; Molecular biology ; Neuroscience ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: The VIP-VPAC2 neuropeptidergic axis is a cellular pacemaking hub of the suprachiasmatic nucleus circadian circuit

    Andrew P. Patton / Mathew D. Edwards / Nicola J. Smyllie / Ryan Hamnett / Johanna E. Chesham / Marco Brancaccio / Elizabeth S. Maywood / Michael H. Hastings

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 17

    Abstract: Circadian activity modulation in the suprachiasmatic nucleus (SCN) is a network-level emergent property that requires neuropeptide VIP signaling, yet the precise cellular mechanisms are unknown. Patton et al. show that cells expressing VIP or its ... ...

    Abstract Circadian activity modulation in the suprachiasmatic nucleus (SCN) is a network-level emergent property that requires neuropeptide VIP signaling, yet the precise cellular mechanisms are unknown. Patton et al. show that cells expressing VIP or its receptor VPAC2 together determine these emergent properties of the SCN.
    Keywords Science ; Q
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: The VIP-VPAC2 neuropeptidergic axis is a cellular pacemaking hub of the suprachiasmatic nucleus circadian circuit

    Andrew P. Patton / Mathew D. Edwards / Nicola J. Smyllie / Ryan Hamnett / Johanna E. Chesham / Marco Brancaccio / Elizabeth S. Maywood / Michael H. Hastings

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 17

    Abstract: Circadian activity modulation in the suprachiasmatic nucleus (SCN) is a network-level emergent property that requires neuropeptide VIP signaling, yet the precise cellular mechanisms are unknown. Patton et al. show that cells expressing VIP or its ... ...

    Abstract Circadian activity modulation in the suprachiasmatic nucleus (SCN) is a network-level emergent property that requires neuropeptide VIP signaling, yet the precise cellular mechanisms are unknown. Patton et al. show that cells expressing VIP or its receptor VPAC2 together determine these emergent properties of the SCN.
    Keywords Science ; Q
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour

    Masao Doi / Iori Murai / Sumihiro Kunisue / Genzui Setsu / Naohiro Uchio / Rina Tanaka / Sakurako Kobayashi / Hiroyuki Shimatani / Hida Hayashi / Hsu-Wen Chao / Yuuki Nakagawa / Yukari Takahashi / Yunhong Hotta / Jun-ichirou Yasunaga / Masao Matsuoka / Michael H. Hastings / Hiroshi Kiyonari / Hitoshi Okamura

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 13

    Abstract: The suprachiasmatic nucleus (SCN) is the central regulator of circadian rhythms. Here the authors identify mouse Gpr176 as a pace modulator of this circadian clock and characterize its mode of action as coupling to Gz rather than Gi subunits. ...

    Abstract The suprachiasmatic nucleus (SCN) is the central regulator of circadian rhythms. Here the authors identify mouse Gpr176 as a pace modulator of this circadian clock and characterize its mode of action as coupling to Gz rather than Gi subunits.
    Keywords Science ; Q
    Language English
    Publishing date 2016-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Signaling role of prokineticin 2 on the estrous cycle of female mice.

    Ling Xiao / Chengkang Zhang / Xiaohan Li / Shiaoching Gong / Renming Hu / Ravikumar Balasubramanian / William F Crowley W / Michael H Hastings / Qun-Yong Zhou

    PLoS ONE, Vol 9, Iss 3, p e

    2014  Volume 90860

    Abstract: The possible signaling role of prokineticin 2 (PK2) and its receptor, prokineticin receptor 2 (PKR2), on female reproduction was investigated. First, the expression of PKR2 and its co-localization with estrogen receptor (ERα) in the hypothalamus was ... ...

    Abstract The possible signaling role of prokineticin 2 (PK2) and its receptor, prokineticin receptor 2 (PKR2), on female reproduction was investigated. First, the expression of PKR2 and its co-localization with estrogen receptor (ERα) in the hypothalamus was examined. Sexually dimorphic expression of PKR2 in the preoptic area of the hypothalamus was observed. Compared to the male mice, there was more widespread PKR2 expression in the preoptic area of the hypothalamus in the female mice. The likely co-expression of PKR2 and ERα in the preoptic area of the hypothalamus was observed. The estrous cycles in female PK2-null, and PKR2-null heterozygous mice, as well as in PK2-null and PKR2-null compound heterozygous mice were examined. Loss of one copy of PK2 or PKR2 gene caused elongated and irregular estrous cycle in the female mice. The alterations in the estrous cycle were more pronounced in PK2-null and PKR2-null compound heterozygous mice. Consistent with these observations, administration of a small molecule PK2 receptor antagonist led to temporary blocking of estrous cycle at the proestrous phase in female mice. The administration of PKR2 antagonist was found to blunt the circulating LH levels. Taken together, these studies indicate PK2 signaling is required for the maintenance of normal female estrous cycles.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity

    Bazbek Davletov / Giampietro Schiavo / Dhevahi Niranjan / Ornella Rossetto / Michael H. Hastings / Marco Pirazzini / Matteo Caleo / Enrico Ferrari / Elizabeth S. Maywood / Laura Restani

    Toxins, Vol 3, Iss 4, Pp 345-

    2011  Volume 355

    Abstract: The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A- ... ...

    Abstract The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A-mediated synaptic silencing include very long duration, high potency and localized action. However, there is a fear of possible side-effects of BoNT/A due to its diffusible nature which may lead to neuromuscular blockade away from the injection site. We recently developed a “protein-stapling” technology which allows re-assembly of BoNT/A from two separate fragments. This technology allowed, for the first time, safe production of this popular neuronal silencing agent. Here we evaluated the re-assembled toxin in several CNS assays and assessed its systemic effects in an animal model. Our results show that the re-assembled toxin is potent in inhibiting CNS function at 1 nM concentration but surprisingly does not exhibit systemic toxicity after intraperitoneal injection even at 200 ng/kg dose. This shows that the re-assembled toxin represents a uniquely safe tool for neuroscience research and future medical applications.
    Keywords botulinum neurotoxin ; nervous system ; protein engineering ; synapse ; SNAREs ; BOTOX ; BITOX ; Medicine ; R
    Language English
    Publishing date 2011-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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