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

doi:10.1083/jcb.200301080

Published online 14 July 2003. doi:10.1083/jcb.200301080

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© The Rockefeller University Press, 0021-9525/2003/7/233 $5.00
The Journal of Cell Biology, Volume 162, Number 2, 233-243

Article

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

Catherine I. Dubreuil, Matthew J. Winton and Lisa McKerracher

Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec H3T 1J4, Canada

Address correspondence to Lisa McKerracher, Université de Montréal, 2900 Edouard-Montpetit, Faculté de médecine, Département de pathologie et biologie cellulaire, Montréal, QC H3T 1J4, Canada. Tel.: (514) 343-6111, ex. 1472. Fax: (514) 282-9990. E-mail: mckerral{at}patho.umontreal.ca

Growth inhibitory proteins in the central nervous system (CNS)block axon growth and regeneration by signaling to Rho, an intracellularGTPase. It is not known how CNS trauma affects the expressionand activation of RhoA. Here we detect GTP-bound RhoA in spinalcord homogenates and report that spinal cord injury (SCI) inboth rats and mice activates RhoA over 10-fold in the absenceof changes in RhoA expression. In situ Rho-GTP detection revealedthat both neurons and glial cells showed Rho activation at SCIlesion sites. Application of a Rho antagonist (C3–05)reversed Rho activation and reduced the number of TUNEL-labeledcells by $~$ 50% in both injured mouse and rat, showing a role foractivated Rho in cell death after CNS injury. Next, we examinedthe role of the p75 neurotrophin receptor (p75^NTR) in Rho signaling.After SCI, an up-regulation of p75^NTR was detected by Westernblot and observed in both neurons and glia. Treatment with C3–05blocked the increase in p75^NTR expression. Experiments withp75^NTR-null mutant mice showed that immediate Rho activationafter SCI is p75^NTR dependent. Our results indicate that blockingoveractivation of Rho after SCI protects cells from p75^NTR-dependentapoptosis.

Key Words: spinal cord injury; RhoA; apoptosis; MAG; p75^NTR

^* Abbreviations used in this paper: CNS, central nervous system;MAG, myelin-associated glycoprotein; NgR, Nogo-66 receptor;p75^NTR, p75 neurotrophin receptor; RBD, Rho-binding domain;SCI, spinal cord injury.

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