Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/43218
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dc.contributor.authorLopes, Carla-
dc.contributor.authorAubert, Sophie-
dc.contributor.authorBourgois-Rocha, Fany-
dc.contributor.authorBarnat, Monia-
dc.contributor.authorRego, Ana Cristina-
dc.contributor.authorDéglon, Nicole-
dc.contributor.authorPerrier, Anselme L.-
dc.contributor.authorHumbert, Sandrine-
dc.date.accessioned2017-09-07T12:45:47Z-
dc.date.available2017-09-07T12:45:47Z-
dc.date.issued2016-
dc.identifier.urihttps://hdl.handle.net/10316/43218-
dc.description.abstractMutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington's disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.por
dc.language.isoporpor
dc.rightsopenAccesspor
dc.subjectAdultpor
dc.subjectAge of Onsetpor
dc.subjectAllelespor
dc.subjectAntigens, Nuclearpor
dc.subjectCells, Culturedpor
dc.subjectDynactin Complexpor
dc.subjectDyneinspor
dc.subjectGenes, Dominantpor
dc.subjectHuman Embryonic Stem Cellspor
dc.subjectHumanspor
dc.subjectHuntingtin Proteinpor
dc.subjectMicrotubule-Associated Proteinspor
dc.subjectNerve Tissue Proteinspor
dc.subjectNeural Stem Cellspor
dc.subjectNuclear Matrix-Associated Proteinspor
dc.subjectPeptidespor
dc.subjectPluripotent Stem Cellspor
dc.subjectPolymorphism, Single Nucleotidepor
dc.subjectProtein Transportpor
dc.subjectRNA Interferencepor
dc.subjectRNA, Small Interferingpor
dc.subjectSpindle Apparatuspor
dc.subjectSubcellular Fractionspor
dc.subjectTrinucleotide Repeat Expansionpor
dc.subjectMutationpor
dc.titleDominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cellspor
dc.typearticle-
degois.publication.firstPagee0148680por
degois.publication.issue2por
degois.publication.titlePLOS ONEpor
dc.peerreviewedyespor
dc.identifier.doi10.1371/journal.pone.0148680por
dc.identifier.doi10.1371/journal.pone.0148680-
degois.publication.volume11por
item.fulltextCom Texto completo-
item.grantfulltextopen-
item.languageiso639-1pt-
item.openairetypearticle-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.orcid0000-0003-0700-3776-
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
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