Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system

被引:333
作者
Dubreuil, CI [1 ]
Winton, MJ [1 ]
McKerracher, L [1 ]
机构
[1] Univ Montreal, Fac Med, Dept Pathol & Biol Cellulaire, Montreal, PQ H3T 1J4, Canada
关键词
spinal cord injury; RhoA; apoptosis; MAG; p75(NTR);
D O I
10.1083/jcb.200301080
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Growth inhibitory proteins in the central nervous system (CNS) block axon growth and regeneration by signaling to Rho, an intracellular GTPase. It is not known how CNS trauma affects the expression and activation of RhoA. Here we detect GTP-bound RhoA in spinal cord homogenates and report that spinal cord injury (SCI) in both rats and mice activates RhoA over 10-fold in the absence of changes in RhoA expression. In situ Rho-GTP detection revealed that both neurons and glial cells showed Rho activation at SCI lesion sites. Application of a Rho antagonist (C3-05) reversed Rho activation and reduced the number of TUNEL-labeled cells by similar to50% in both injured mouse and rat, showing a role for activated Rho in cell death after CNS injury. Next, we examined the role of the p75 neurotrophin receptor (P75(NTR)) in Rho signaling. After SCI, an up-regulation of p75(NTR) was detected by Western blot and observed in both neurons and glia. Treatment with C3-05 blocked the increase in p75(NTR) expression. Experiments with p75(NTR)- null mutant mice showed that immediate Rho activation after SCI is p75(NTR) dependent. Our results indicate that blocking overactivation of Rho after SCI protects cells from p75(NTR)- dependent apoptosis.
引用
收藏
页码:233 / 243
页数:11
相关论文
共 65 条
[1]   Rho signals to cell growth and apoptosis [J].
Aznar, S ;
Lacal, JC .
CANCER LETTERS, 2001, 165 (01) :1-10
[2]   ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury [J].
Beattie, MS ;
Harrington, AW ;
Lee, R ;
Kim, JY ;
Boyce, SL ;
Longo, FM ;
Bresnahan, JC ;
Hempstead, BL ;
Yoon, SO .
NEURON, 2002, 36 (03) :375-386
[3]   Inactivation of the small GTPase Rho disrupts cellular attachment and induces adhesion-dependent and adhesion-independent apoptosis [J].
Bobak, D ;
Moorman, J ;
Guanzon, A ;
Gilmer, L ;
Hahn, C .
ONCOGENE, 1997, 15 (18) :2179-2189
[4]   Dexamethasone reduces the expression of p75 neurotrophin receptor and apoptosis in contused spinal cord [J].
Brandoli, C ;
Shi, BT ;
Pflug, B ;
Andrews, P ;
Wrathall, JR ;
Mocchetti, I .
MOLECULAR BRAIN RESEARCH, 2001, 87 (01) :61-70
[5]   Oligodendroglial apoptosis occurs along degenerating axons and is associated with Fas and p75 expression following spinal cord injury in the rat [J].
Casha, S ;
Yu, WR ;
Fehlings, MG .
NEUROSCIENCE, 2001, 103 (01) :203-218
[6]  
Cheema SS, 1996, J NEUROSCI RES, V46, P239, DOI 10.1002/(SICI)1097-4547(19961015)46:2<239::AID-JNR12>3.0.CO
[7]  
2-Y
[8]   Upregulation of neurotoxic serine proteases, prothrombin, and protease-activated receptor 1 early after spinal cord injury [J].
Citron, BA ;
Smirnova, IV ;
Arnold, PM ;
Festoff, BW .
JOURNAL OF NEUROTRAUMA, 2000, 17 (12) :1191-1203
[9]   Genomic analysis of metastasis reveals an essential role for RhoC [J].
Clark, EA ;
Golub, TR ;
Lander, ES ;
Hynes, RO .
NATURE, 2000, 406 (6795) :532-535
[10]   Rho GTPase signalling pathways in the morphological changes associated with apoptosis [J].
Coleman, ML ;
Olson, MF .
CELL DEATH AND DIFFERENTIATION, 2002, 9 (05) :493-504