Neurodevelopmental abnormalities in neurosphere-derived neural stem cells from SMN-depleted mice

被引：31

作者：

Shafey, Dina ^{[1
,2
,3
]}

MacKenzie, Alex E. ^{[4
,5
]}

Kothary, Rashmi ^{[1
,2
,3
,6
]}

机构：

[1] Ottawa Hlth Res Inst, Ottawa, ON K1H 8L6, Canada

[2] Univ Ottawa, Ctr Neuromuscular Dis, Ottawa, ON, Canada

[3] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada

[4] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada

[5] Eastern Ontario Res Inst, Childrens Hosp, Solange Gauthier Karsh, Ottawa, ON, Canada

[6] Univ Ottawa, Dept Med, Ottawa, ON, Canada

来源：

JOURNAL OF NEUROSCIENCE RESEARCH | 2008年 / 86卷 / 13期

基金：

加拿大健康研究院;

关键词：

spinal muscular atrophy; survival motor neuron; neurospheres; neurodegeneration; axon outgrowth and branching;

D O I：

10.1002/jnr.21743

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Spinal muscular atrophy (SMA) is a genetic disorder caused by depletion of survival motor neuron (SMN) protein and characterized by degeneration of alpha-motor neurons in the spinal cord. We investigated the morphology and differentiation of neurosphere-derived neural stem cells (NSCs) generated from the brains of a hypomorphic series of SMA mice. Neurospheres from the Smn(-/-);SMN2 mice, which represent a model of very severe SMA, produced NSCs with increased proliferation during growth and differentiation. These cells produced fewer Tuj1-positive neuronal cells, which displayed morphological alterations and had fewer and shorter neurites. The decrease in the number of Tuj1-positive cells was not a result of enhanced apoptosis but was accompanied by an increase in the number of nestin-positive cells. These results provide insight into the most severe model of SMA, in which SMN is nearly completely depleted, and suggest that SMN has a role in neurodevelopment as well as in neuromaintenance. Our work raises the possibility that SMN depletion affects neurodevelopment and neuromaintenance to varying extents, leading to SMA pathogenesis. (C) 2008 Wiley-Liss, Inc.

引用

页码：2839 / 2847

页数：9

共 29 条

[1] Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study [J].

Bahn, S ;

Mimmack, M ;

Ryan, M ;

Caldwell, MA ;

Jaunlaux, E ;

Starkey, M ;

Svendsen, CN ;

Emson, P .

LANCET, 2002, 359 (9303) :310-315

[2] Smn depletion alters profilin II expression and leads to upregulation of the RhoA/ROCK pathway and defects in neuronal integrity [J].

Bowerman, Melissa ;

Shafey, Dina ;

Kothary, Rashmi .

JOURNAL OF MOLECULAR NEUROSCIENCE, 2007, 32 (02) :120-131

[3] Altered differentiation of neural stem cells in fragile X syndrome [J].

Castrén, M ;

Tervonen, T ;

Kärkkäinen, V ;

Heinonen, S ;

Castrén, E ;

Larsson, K ;

Bakker, CE ;

Oostra, BA ;

Åkerman, K .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (49) :17834-17839

[4] Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice [J].

Chen, JH ;

Magavi, SSP ;

Macklis, JD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (46) :16357-16362

[5] Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo [J].

Chi, L. ;

Ke, Y. ;

Luo, C. ;

Gozal, D. ;

Liu, R. .

NEUROSCIENCE, 2007, 144 (03) :991-1003

[6] The survival motor neuron protein in spinal muscular atrophy [J].

Coovert, DD ;

Le, TT ;

McAndrew, PE ;

Strasswimmer, J ;

Crawford, TO ;

Mendell, JR ;

Coulson, SE ;

Androphy, EJ ;

Prior, TW ;

Burghes, AHM .

HUMAN MOLECULAR GENETICS, 1997, 6 (08) :1205-1214

[7]

Daadi MM, 1999, J NEUROSCI, V19, P4484

[8] Cloning, characterization, and copy number of the murine survival motor neuron gene: Homolog of the spinal muscular atrophy-determining gene [J].

DiDonato, CJ ;

Chen, XN ;

Noya, D ;

Korenberg, JR ;

Nadeau, JH ;

Simard, LR .

GENOME RESEARCH, 1997, 7 (04) :339-352

[9] Mammalian neural stem cells [J].

Gage, FH .

SCIENCE, 2000, 287 (5457) :1433-1438

[10] IS KUGELBERG-WELANDER SPINAL MUSCULAR-ATROPHY A FETAL DEFECT [J].

HAUSMANOWAPETRUSEWICZ, I ;

FIDZIANSKA, A ;

NIEBROJDOBOSZ, I ;

STRUGALSKA, MH .

MUSCLE & NERVE, 1980, 3 (05) :389-402

← 1 2 3 →