期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 30, 页码 10034-10040出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0715-14.2014
关键词
cortical neurogenesis; Huntington disease; mitosis; spindle orientation
资金
- Agence Nationale pour la Recherche [ANR-09-BLAN-0080]
- Fondation pour la Recherche Medicale
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale
- Institut Curie
- Institut Curie Ph.D. fellowship
- NERF Ile de France fellowship
- CIFRE fellowship [2012-0401]
- Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0080] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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