title: Mutant huntingtin affects cortical progenitor cell division and development of the mouse neocortex.
abstract: A polyglutamine expansion in huntingtin (HTT) causes the specific death of adult neurons in Huntington's disease (HD). Most studies have thus focused on mutant HTT (mHTT) toxicity in adulthood, and its developmental effects have been largely overlooked. We found that mHTT caused mitotic spindle misorientation in cultured cells by altering the localization of dynein, NuMA, and the p150(Glued) subunit of dynactin to the spindle pole and cell cortex and of CLIP170 and p150(Glued) to microtubule plus-ends. mHTT also affected spindle orientation in dividing mouse cortical progenitors, altering the thickness of the developing cortex. The serine/threonine kinase Akt, which regulates HTT function, rescued the spindle misorientation caused by the mHTT, by serine 421 (S421) phosphorylation, in cultured cells and in mice. Thus, cortical development is affected in HD, and this early defect can be rescued by HTT phosphorylation at S421.
authors: Institut Curie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 3306, and Institut National de la Santé et de la Recherche Médicale U1005, Orsay 91405, France, and.
authors: Maria
authors: M
authors: Molina-Calavita
authors: Institut Curie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 3306, and Institut National de la Santé et de la Recherche Médicale U1005, Orsay 91405, France, and.
authors: Monia
authors: M
authors: Barnat
authors: Institut Curie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 3306, and Institut National de la Santé et de la Recherche Médicale U1005, Orsay 91405, France, and.
authors: Salah
authors: S
authors: Elias
authors: Institut Curie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 3306, and Institut National de la Santé et de la Recherche Médicale U1005, Orsay 91405, France, and.
authors: Esther
authors: E
authors: Aparicio
authors: Institut Curie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 144, Paris 75005, France.
authors: Matthieu
authors: M
authors: Piel
authors: Institut Curie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 3306, and Institut National de la Santé et de la Recherche Médicale U1005, Orsay 91405, France, and sandrine.humbert@curie.fr.
authors: Sandrine
authors: http://orcid.org/0000-0002-9501-2658
authors: S
authors: Humbert
mesh_terms: D000818:Animals; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D019579:Neocortex / Q000254:growth & development* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics; D013234:Stem Cells / Q000473:pathology*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
keywords: Huntington disease; cortical neurogenesis; mitosis; spindle orientation