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dc.contributor.authorSmyllie, Nicola J
dc.contributor.authorBagnall, James
dc.contributor.authorKoch, Alex A
dc.contributor.authorNiranjan, Dhevahi
dc.contributor.authorPolidarova, Lenka
dc.contributor.authorChesham, Johanna E
dc.contributor.authorChin, Jason
dc.contributor.authorPartch, Carrie L
dc.contributor.authorLoudon, Andrew SI
dc.contributor.authorHastings, Michael
dc.date.accessioned2022-02-21T02:02:17Z
dc.date.available2022-02-21T02:02:17Z
dc.date.issued2022-01-25
dc.identifier.issn0027-8424
dc.identifier.otherPMC8795536
dc.identifier.other35046033
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334252
dc.description.abstractThe ∼20,000 cells of the suprachiasmatic nucleus (SCN), the master circadian clock of the mammalian brain, coordinate subordinate cellular clocks across the organism, driving adaptive daily rhythms of physiology and behavior. The canonical model for SCN timekeeping pivots around transcriptional/translational feedback loops (TTFL) whereby PERIOD (PER) and CRYPTOCHROME (CRY) clock proteins associate and translocate to the nucleus to inhibit their own expression. The fundamental individual and interactive behaviors of PER and CRY in the SCN cellular environment and the mechanisms that regulate them are poorly understood. We therefore used confocal imaging to explore the behavior of endogenous PER2 in the SCN of PER2::Venus reporter mice, transduced with viral vectors expressing various forms of CRY1 and CRY2. In contrast to nuclear localization in wild-type SCN, in the absence of CRY proteins, PER2 was predominantly cytoplasmic and more mobile, as measured by fluorescence recovery after photobleaching. Virally expressed CRY1 or CRY2 relocalized PER2 to the nucleus, initiated SCN circadian rhythms, and determined their period. We used translational switching to control CRY1 cellular abundance and found that low levels of CRY1 resulted in minimal relocalization of PER2, but yet, remarkably, were sufficient to initiate and maintain circadian rhythmicity. Importantly, the C-terminal tail was necessary for CRY1 to localize PER2 to the nucleus and to initiate SCN rhythms. In CRY1-null SCN, CRY1Δtail opposed PER2 nuclear localization and correspondingly shortened SCN period. Through manipulation of CRY proteins, we have obtained insights into the spatiotemporal behaviors of PER and CRY sitting at the heart of the TTFL molecular mechanism.
dc.languageeng
dc.publisherProceedings of the National Academy of Sciences
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 7505876
dc.sourceessn: 1091-6490
dc.subjectFRAP
dc.subjectCry1
dc.subjectScn
dc.subjectNuclear Retention
dc.subjectIntracellular Mobility
dc.titleCryptochrome proteins regulate the circadian intracellular behavior and localization of PER2 in mouse suprachiasmatic nucleus neurons.
dc.typeArticle
dc.date.updated2022-02-21T02:02:16Z
prism.issueIdentifier4
prism.publicationNameProc Natl Acad Sci U S A
prism.volume119
dc.identifier.doi10.17863/CAM.81665
dcterms.dateAccepted2021-11-16
rioxxterms.versionofrecord10.1073/pnas.2113845119
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidSmyllie, Nicola J [0000-0002-6324-1421]
dc.contributor.orcidBagnall, James [0000-0003-1735-5855]
dc.contributor.orcidKoch, Alex A [0000-0002-0592-331X]
dc.contributor.orcidChesham, Johanna E [0000-0002-8981-2667]
dc.contributor.orcidChin, Jason [0000-0003-1219-4757]
dc.contributor.orcidPartch, Carrie L [0000-0002-4677-2861]
dc.contributor.orcidLoudon, Andrew SI [0000-0003-3648-445X]
dc.contributor.orcidHastings, Michael [0000-0001-8576-6651]
dc.identifier.eissn1091-6490
pubs.funder-project-idMedical Research Council (MC_U105170643)
pubs.funder-project-idNIGMS NIH HHS (R35 GM141849, R01 GM107069)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/P017347/1)
cam.issuedOnline2022-01-19


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International