Mutant Huntingtin Affects Cortical Progenitor Cell Division and Development of the Mouse Neocortex

被引：66

作者：

Molina-Calavita, Maria ^{[1
,2
,3
]}

Barnat, Monia ^{[1
,2
,3
]}

Elias, Salah ^{[1
,2
,3
]}

Aparicio, Esther ^{[1
,2
,3
]}

Piel, Matthieu ^{[1
,4
]}

Humbert, Sandrine ^{[1
,2
,3
]}

机构：

[1] Inst Curie, F-91405 Orsay, France

[2] Ctr Natl Rech Sci, Unite Mixte Rech 3306, F-91405 Orsay, France

[3] Inst Natl Sante & Rech Med, U1005, F-91405 Orsay, France

[4] Ctr Natl Rech Sci, Unite Mixte Rech 144, F-75005 Paris, France

来源：

JOURNAL OF NEUROSCIENCE | 2014年 / 34卷 / 30期

关键词：

cortical neurogenesis; Huntington disease; mitosis; spindle orientation; MITOTIC SPINDLE ORIENTATION; DISEASE GENE HOMOLOG; EMBRYONIC LETHALITY; TRANSPORT; NEURONS; PATHWAY; MICE; HDH; PHOSPHORYLATION; NEUROGENESIS;

D O I：

10.1523/JNEUROSCI.0715-14.2014

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：10034 / 10040

页数：7

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