Huntingtin Is Required for Mitotic Spindle Orientation and Mammalian Neurogenesis

• DOI: 10.1016/j.neuron.2010.06.027
• Publication Date: 2010-08-12T08:49:12Z
• Authors: Juliette D. Godin; Kelly Colombo; Maria Molina-Cala...; Guy Keryer; Diana Zala; Bénédicte C. Charrin; Paula Dietrich; Marie-Laure Volvert; François Guillemot; Ioannis Dragatsis; Yohanns Bellaiche; Frédéric Saudou; Laurent Nguyen; Sandrine Humbert
• Keywords: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Neuroscience(all); Neurogenesis; DEVBIO; Mice, Transgenic; Spindle Apparatus; Cell Enlargement; Microtubules; MOLNEURO; Mice; 03 medical and health sciences; Animals; Drosophila Proteins; Humans; Cells, Cultured; Neurons; Huntingtin Protein; 0303 health sciences; [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis; [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis; Drosophila melanogaster; CELLBIO; Microtubule-Associated Proteins; HeLa Cells

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.