The role of p75(NTR) in spinal cord injury in mice

Abstract

Spinal cord injury causes both immediate and delayed (secondary) injury responses that result in tissue damage over time. Oligodendrocytes, the myelinating cells of the central nervous system, are particularly vulnerable to secondary injury and are known to undergo apoptosis at delayed time points. I was interested in understanding the mechanism underlying the delayed cell death response, and developed a mouse model of contusive spinal cord injury to investigate the possible role of p75^NTR, the common neurotrophin receptor. p75^NTR is a bifunctional protein capable of transducing either a survival or death signal to cells. Neurotrophin induced cell death mediated by p75^NTR has been well described in neuronal systems, and has been suggested as a mechanism underlying oligodendrocyte cell death. By using the mouse model I was able to examine the injury response in a mouse with a targeted mutation in the ligand binding domain of p75^NTR. p75^NTR is not normally expressed in spinal cord oligodendrocytes but I found a significant upregulation after injury in wild-type mice. I hypothesized that delayed oligodendrocyte cell death was mediated by p75^NTR. Immunocolocalization of an oligodendrocyte marker with p75^NTR and TUNEL, an indicator of apoptosis, supported the hypothesis in wild-type mice. An analysis of oligodendrocyte cell death in p75^exonIII mutant mice revealed that the mutation did not affect the time course and extent of oligodendrocyte apoptosis. There was also a shift in kinetics of the injury response. In p75^exonIII mutant mice, the injury was larger at the epicenter but more localized and confined to the impact site, and there was a delay in lesion progression rostral and caudal. Most notably, there was a significant increase in oligodendrocyte density at early time points, compared to the significant cell loss seen in wild-type mice. Taken together, these results suggest the p75^exonIII mutant mouse may have an enhanced repair potential after injury at early time points. More importantly, the ligand-binding domain of p75^NTR is not necessary for oligodendrocyte apoptosis; this activity may be mediated by interactions with the intracellular domain of the receptor.