Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.
Huntingtin is the protein mutated in Huntington's disease, a devastating neurodegenerative disorder. We demonstrate here that huntingtin is essential to control mitosis. Huntingtin is localized at spindle poles during mitosis. RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein. This leads to increased apoptosis following mitosis of adherent cells in vitro. In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos. This function is conserved in Drosophila, the specific disruption of Drosophila huntingtin in neuroblast precursors leading to spindle misorientation. Moreover, Drosophila huntingtin restores spindle misorientation in mammalian cells. These findings reveal an unexpected role for huntingtin in dividing cells, with potential important implications in health and disease.
Godin
Juliette D
JD
Institut Curie, Orsay F-91405, France.
Colombo
Kelly
K
Molina-Calavita
Maria
M
Keryer
Guy
G
Zala
Diana
D
Charrin
Bénédicte C
BC
Dietrich
Paula
P
Volvert
Marie-Laure
ML
Guillemot
François
F
Dragatsis
Ioannis
I
Bellaiche
Yohanns
Y
Saudou
Frédéric
F
Nguyen
Laurent
L
Humbert
Sandrine
S
D000818:Animals; D049108:Cell Enlargement; D002478:Cells, Cultured; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000502:physiology*; D008870:Microtubules / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D008941:Spindle Apparatus / Q000502:physiology*
D029721:Drosophila Proteins; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins