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dc.contributor.authorCagnetta, Robertaen
dc.contributor.authorWong, Hovy Ho-Waien
dc.contributor.authorFrese, Christian Ken
dc.contributor.authorMallucci, Giovannaen
dc.contributor.authorKrijgsveld, Jeroenen
dc.contributor.authorHolt, Christineen
dc.date.accessioned2018-12-15T00:30:50Z
dc.date.available2018-12-15T00:30:50Z
dc.date.issued2019-02en
dc.identifier.issn1097-2765
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286998
dc.description.abstractLocal translation is rapidly regulated by extrinsic signals during neural wiring but its control mechanisms remain elusive. Here, we show that the extracellular cue Sema3A induces an initial burst in local translation that precisely controls the phosphorylation of the translation initiation factor eIF2α via the Unfolded Protein Response (UPR) kinase, PERK. Strikingly, in contrast to canonical UPR signaling, the Sema3A-induced eIF2α phosphorylation bypasses global translational repression and underlies an increase in local translation through differential activity of eIF2B, mediated by Protein Phosphatase 1. Ultrasensitive proteomic analysis on axons reveals 75 proteins translationally controlled via the Sema3A-p-eIF2α pathway. These include proteostasis- and actin cytoskeleton-related proteins, but not canonical stress markers. Finally, we show that PERK signaling is needed for directional axon migration and visual pathway development in vivo. Thus, our findings reveal a noncanonical eIF2 signaling pathway that controls selective changes in axon translation and is required for neural wiring.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.subjectAxonsen
dc.subjectRetinal Ganglion Cellsen
dc.subjectAnimalsen
dc.subjectXenopus laevisen
dc.subjecteIF-2 Kinaseen
dc.subjectEukaryotic Initiation Factor-2Ben
dc.subjectXenopus Proteinsen
dc.subjectSemaphorin-3Aen
dc.subjectEukaryotic Initiation Factor-2en
dc.subjectTissue Culture Techniquesen
dc.subjectProteomicsen
dc.subjectSignal Transductionen
dc.subjectPhosphorylationen
dc.subjectFemaleen
dc.subjectMaleen
dc.subjectNeurogenesisen
dc.subjectProtein Interaction Mapsen
dc.titleNoncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring.en
dc.typeArticle
prism.endingPage489.e5
prism.issueIdentifier3en
prism.publicationDate2019en
prism.publicationNameMolecular cellen
prism.startingPage474
prism.volume73en
dc.identifier.doi10.17863/CAM.34307
dcterms.dateAccepted2018-11-13en
rioxxterms.versionofrecord10.1016/j.molcel.2018.11.013en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-02en
dc.contributor.orcidWong, Hovy Ho-Wai [0000-0003-3317-478X]
dc.contributor.orcidFrese, Christian K [0000-0001-7919-4642]
dc.contributor.orcidMallucci, Giovanna [0000-0001-8504-1191]
dc.contributor.orcidHolt, Christine [0000-0003-2829-121X]
dc.identifier.eissn1097-4164
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (085314/Z/08/Z)
pubs.funder-project-idEuropean Research Council (322817)
pubs.funder-project-idWellcome Trust (203249/Z/16/Z)
pubs.funder-project-idBBSRC (1366878)
pubs.funder-project-idECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647479)
pubs.funder-project-idUK Dementia Research Institute (DRICam17/18)
cam.orpheus.successThu Jan 30 10:53:48 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-02-28


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