Huntingtin Is Required for Mitotic Spindle Orientation and Mammalian Neurogenesis

被引：208

作者：

Godin, Juliette D. ^{[1
,2
,3
]}

Colombo, Kelly ^{[1
,2
,3
]}

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

Keryer, Guy ^{[1
,2
,3
]}

Zala, Diana ^{[1
,2
,3
]}

Charrin, Benedicte C. ^{[1
,2
,3
]}

Dietrich, Paula ^{[4
]}

Volvert, Marie-Laure ^{[5
]}

Guillemot, Francois ^{[6
]}

Dragatsis, Ioannis ^{[4
]}

Bellaiche, Yohanns ^{[1
,7
]}

Saudou, Frederic ^{[1
,2
,3
]}

Nguyen, Laurent ^{[5
]}

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

机构：

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

[2] CNRS, UMR 3306, F-91405 Orsay, France

[3] INSERM, U1005, F-91405 Orsay, France

[4] Univ Tennessee, Hlth Sci Ctr, Dept Physiol, Memphis, TN 38163 USA

[5] Univ Liege, Dev Neurobiol Unit, GIGA Neurosci, B-4000 Liege, Belgium

[6] Natl Inst Med Res, Div Mol Neurobiol, London NW7 1AA, England

[7] Univ Paris 06, CNRS, U934, UMR 3215,INSERM, F-75248 Paris, France

来源：

NEURON | 2010年 / 67卷 / 03期

基金：

瑞士国家科学基金会;

关键词：

ASYMMETRIC CELL-DIVISION; DISEASE GENE HOMOLOG; NEURAL STEM-CELLS; WILD-TYPE; DROSOPHILA NEUROBLASTS; CAENORHABDITIS-ELEGANS; EMBRYONIC LETHALITY; CYTOPLASMIC DYNEIN; BINDING-PROTEIN; BUDDING YEAST;

D O I：

10.1016/j.neuron.2010.06.027

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：392 / 406

页数：15

共 69 条

[1] Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons [J].

Anne, Sandrine L. ;

Saudou, Frederic ;

Humbert, Sandrine .

JOURNAL OF NEUROSCIENCE, 2007, 27 (27) :7318-7328

[2] Huntington's disease:: from huntingtin function and dysfunction to therapeutic strategies [J].

Borrell-Pages, M. ;

Zala, D. ;

Humbert, S. ;

Saudou, F. .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2006, 63 (22) :2642-2660

[3] The Drosophila NuMA homolog mud regulates spindle orientation in asymmetric cell division [J].

Bowman, Sarah K. ;

Neumueller, Ralph A. ;

Novatchkova, Maria ;

Du, Quansheng ;

Knoblich, Juergen A. .

DEVELOPMENTAL CELL, 2006, 10 (06) :731-742

[4] Dynein and dynactin are localized to astral microtubules and at cortical sites in mitotic epithelial cells [J].

Busson, S ;

Dujardin, D ;

Moreau, A ;

Dompierre, J ;

De Mey, JR .

CURRENT BIOLOGY, 1998, 8 (09) :541-544

[5] At regulates centrosome migration and spindle orientation in the early Drosophila melanogaster embryo [J].

Buttrick, Graham J. ;

Beaumont, Luke M. A. ;

Leitch, Jessica ;

Yau, Christopher ;

Hughes, Julian R. ;

Wakefield, James G. .

JOURNAL OF CELL BIOLOGY, 2008, 180 (03) :537-548

[6] Normal huntingtin function: An alternative approach to Huntington's disease [J].

Cattaneo, E ;

Zuccato, C ;

Tartari, M .

NATURE REVIEWS NEUROSCIENCE, 2005, 6 (12) :919-930

[7] Huntingtin facilitates dynein/dynactin-mediated vesicle transport [J].

Caviston, Juliane P. ;

Ross, Jennifer L. ;

Antony, Sheila M. ;

Tokito, Mariko ;

Holzbaur, Erika L. F. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (24) :10045-10050

[8] Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons [J].

Colin, Emilie ;

Zala, Diana ;

Liot, Geraldine ;

Rangone, Helene ;

Borrell-Pages, Maria ;

Li, Xiao-Jiang ;

Saudou, Frederic ;

Humbert, Sandrine .

EMBO JOURNAL, 2008, 27 (15) :2124-2134

[9] LIS1, CLIP-170's key to the dynein/dynactin pathway [J].

Coquelle, FM ;

Caspi, M ;

Cordelières, FP ;

Dompierre, JP ;

Dujardin, DL ;

Koifman, C ;

Martin, P ;

Hoogenraad, CC ;

Akhmanova, A ;

Galjart, N ;

De Mey, JR ;

Reiner, O .

MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (09) :3089-3102

[10] Congenital hydrocephalus associated with abnormal subcommissural organ in mice lacking huntingtin in Wnt1 cell lineages [J].

Dietrich, Paula ;

Shanmugasundaram, Revathi ;

E, Shuyu ;

Dragatsis, Ioannis .

HUMAN MOLECULAR GENETICS, 2009, 18 (01) :142-150

← 1 2 3 4 5 6 7 →