Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells.

Détails

Ressource 1Télécharger: BIB_55A9BBB6E4AE.P001.pdf (3776.78 [Ko])
Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_55A9BBB6E4AE
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells.
Périodique
Plos One
Auteur(s)
Lopes C., Aubert S., Bourgois-Rocha F., Barnat M., Rego A.C., Déglon N., Perrier A.L., Humbert S.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
11
Numéro
2
Pages
e0148680
Langue
anglais
Résumé
Mutations 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.
Pubmed
Web of science
Open Access
Oui
Création de la notice
20/02/2016 16:28
Dernière modification de la notice
20/08/2019 15:10
Données d'usage