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dc.contributor.authorJardin, Nicolas
dc.contributor.authorGiudicelli, François
dc.contributor.authorTen Martín, Daniel
dc.contributor.authorVitrac, Anaïs
dc.contributor.authorDe Gois, Stéphanie
dc.contributor.authorAllison, Rachel
dc.contributor.authorHouart, Corinne
dc.contributor.authorReid, Evan
dc.contributor.authorHazan, Jamilé
dc.contributor.authorFassier, Coralie
dc.date.accessioned2018-11-01T14:04:01Z
dc.date.available2018-11-01T14:04:01Z
dc.date.issued2018-09-12
dc.identifier.issn0950-1991
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284535
dc.description.abstractFunctional analyses of genes responsible for neurodegenerative disorders have unveiled crucial links between neurodegenerative processes and key developmental signalling pathways. Mutations in SPG4-encoding spastin cause hereditary spastic paraplegia (HSP). Spastin is involved in diverse cellular processes that couple microtubule severing to membrane remodelling. Two main spastin isoforms are synthesised from alternative translational start sites (M1 and M87). However, their specific roles in neuronal development and homeostasis remain largely unknown. To selectively unravel their neuronal function, we blocked spastin synthesis from each initiation codon during zebrafish development and performed rescue analyses. The knockdown of each isoform led to different motor neuron and locomotion defects, which were not rescued by the selective expression of the other isoform. Notably, both morphant neuronal phenotypes were observed in a CRISPR/Cas9 spastin mutant. We next showed that M1 spastin, together with HSP proteins atlastin 1 and NIPA1, drives motor axon targeting by repressing BMP signalling, whereas M87 spastin acts downstream of neuropilin 1 to control motor neuron migration. Our data therefore suggest that defective BMP and neuropilin 1 signalling may contribute to the motor phenotype in a vertebrate model of spastin depletion.
dc.description.sponsorshipSee acknowledgements in paper. In addition, the following funder statement has been added to the acknowledgements section of the paper at the proof stage (and is not in the attached manuscript file): ER and RA are supported by grant MR/M00046X/1 from the UK Medical Research Council
dc.format.mediumElectronic
dc.languageeng
dc.publisherThe Company of Biologists
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAxons
dc.subjectMotor Neurons
dc.subjectCell Line
dc.subjectCOS Cells
dc.subjectAnimals
dc.subjectZebrafish
dc.subjectHumans
dc.subjectSpastic Paraplegia, Hereditary
dc.subjectGTP-Binding Proteins
dc.subjectZebrafish Proteins
dc.subjectBone Morphogenetic Proteins
dc.subjectMembrane Proteins
dc.subjectNeuropilin-1
dc.subjectProtein Isoforms
dc.subjectCell Movement
dc.subjectGene Knockout Techniques
dc.subjectCRISPR-Cas Systems
dc.subjectSpastin
dc.subjectChlorocebus aethiops
dc.titleBMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.
dc.typeArticle
prism.issueIdentifier17
prism.publicationDate2018
prism.publicationNameDevelopment
prism.volume145
dc.identifier.doi10.17863/CAM.31909
dcterms.dateAccepted2018-07-16
rioxxterms.versionofrecord10.1242/dev.162701
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09-12
dc.contributor.orcidJardin, Nicolas [0000-0003-1216-2894]
dc.contributor.orcidHouart, Corinne [0000-0002-2062-3964]
dc.contributor.orcidReid, Evan [0000-0003-1623-7304]
dc.contributor.orcidFassier, Coralie [0000-0003-3015-4281]
dc.identifier.eissn1477-9129
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/M00046X/1)
cam.issuedOnline2018-01-01


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