Sci. STKE, 8 March 2005
NEUROBIOLOGY Signaling Neuronal Injury
Damage to a nerve terminal or an axon can lead to either neuronal regeneration or neuronal death. However, the mechanisms whereby information about injury to a distal axon are conveyed to the cell body are unclear. Now two groups have shed light on different pieces of this puzzle. Among the early sequelae of axotomy are increases in the activity of the transcription factor c-Jun and appearance of activated c-Jun N-terminal kinase (JNK) in the cell body. Cavalli et al. investigated the hypothesis that Sunday Driver (Syd), a scaffolding protein that binds both JNK and the anterograde molecular motor kinesin-1, participates with JNK in a vesicular system that transports signaling molecules to particular subcellular locations in response to injury. After determining that both Syd and JNK3 from mouse sciatic nerve extracts existed in both membrane-associated and soluble pools, the authors used immunofluorescence to show that Syd was associated with axonal vesicles. High-resolution images of single axons revealed partial colocalization of Syd and JNK, and the two proteins coimmunoprecipitated. Coimmunoprecipitation and high-resolution imaging indicated that Syd also interacted with the dynein-dynactin motor complex (which is involved in retrograde transport). Sciatic nerve ligation experiments showed that Syd and JNK3 were transported in both retrograde and anterograde directions and that injury increased Syd association with membranes. Sciatic nerve injury stimulated an increase in JNK phosphorylation locally and, after a delay, in sensory neuron cell bodies in the dorsal root ganglia (DRG). Double ligation of the nerve indicated that, following nerve injury, phosphorylated JNK and Syd were primarily transported retrogradely. Nerve injury also appeared to promote association between Syd and the dynein-dynactin complex. Thus, the authors propose that Syd, by transporting activated JNK back to the cell body, may play a critical role in mediating the "injury" signal.
In a second study, Perlson et al. implicated the intermediate filament protein vimentin in retrograde transport of activated forms of the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 (ERK1/2) in response to injury. Injury to mouse sciatic nerve led to an increase in soluble vimentin in axoplasm, which depended on local translation and calpain activity. Injury promoted an increase in phosphorylated ERK1/2 (pERK) and of the association of vimentin with dynein and importin α and β as well as pERK. Both vimentin and pERK were transported retrogradely with dynein after nerve injury, with pERK lost from the complex after arrival at the DRG. The authors used mice lacking vimentin to show that pERK association with the dynein complex depended on vimentin. Moreover, phosphorylation of the transcription factor Elk1 (an ERK target) in response to injury was lost in the vimentin-free mice, and regenerative responses of DRG neurons were attenuated. A similar loss of regenerative capacity was seen in the DRG neurons of rats treated with a synthetic peptide that blocked the association of vimentin with pERK or with a mitogen-activated or extracellular signal-regulated protein kinase kinase inhibitor. Thus, the association of soluble vimentin with pERK and a dynein-importin complex appears to provide a mechanism for the retrograde transport of activated MAPKs in response to injury.
E. Perlson, S. Hanz, K. Ben-Yaakov, Y. Segal-Ruder, R. Seger, M. Fainzilber, Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve. Neuron 45, 715-726 (2005). [PubMed]
Citation: Signaling Neuronal Injury. Sci. STKE 2005, tw88 (2005).
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