Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system.
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 approximately 50% 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 (p75NTR) in Rho signaling. After SCI, an up-regulation of p75NTR was detected by Western blot and observed in both neurons and glia. Treatment with C3-05 blocked the increase in p75NTR expression. Experiments with p75NTR-null mutant mice showed that immediate Rho activation after SCI is p75NTR dependent. Our results indicate that blocking overactivation of Rho after SCI protects cells from p75NTR-dependent apoptosis.
Dubreuil
Catherine I
CI
Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, QC H3T 1J4, Canada.
Winton
Matthew J
MJ
McKerracher
Lisa
L
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D020318:Rats, Long-Evans; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism*; D015854:Up-Regulation; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D015415:Biomarkers; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020742:rhoA GTP-Binding Protein