Peripheral Axotomy Induces Long-Term c-Jun Amino-Terminal Kinase-1 Activation and Activator Protein-1 Binding Activity by c-Jun and junD in Adult Rat Dorsal Root GangliaIn Vivo

Abstract

One of the earliest documented molecular events after sciatic nerve injury in adult rats is the rapid, long-term upregulation of the immediate early gene transcription factor c-Jun mRNA and protein in lumbar dorsal root ganglion (DRG) neurons, suggesting that c-Jun may regulate genes that are important both in the early post-injury period and during later peripheral axonal regeneration. However, neither the mechanism through which c-Jun protein is increased nor the level of its post-injury transcriptional activity in axotomized DRGs has been characterized. To determine whether transcriptional activation of c-Jun occurs in response to nerve injury in vivo and is associated with axonal regeneration, we have assayed axotomized adult rat DRGs for evidence of jun kinase activation, c-Jun phosphorylation, and activator protein-1 (AP-1) binding. We report that sciatic nerve transection resulted in chronic activation of c-Jun amino-terminal kinase-1 (JNK) in L4/L5 DRGs concomitant with c-Jun amino-terminal phosphorylation in neurons, and lasting AP-1 binding activity, with both c-Jun and JunD participating in DNA binding complexes. The timing of JNK activation was dependent on the distance of the axotomy site from the DRGs, suggesting the requirement for a retrograde transport-mediated signal. AP-1 binding and c-Jun protein returned to basal levels in DRGs as peripheral regeneration was completed but remained elevated in the case of chronic sprouting, indicating that c-Jun may regulate target genes that are involved in axonal outgrowth.

Activation of Rac GTPase by p75 Is Necessary for c-junN-Terminal Kinase-Mediated Apoptosis

“…p75 activates JNK1 and 3 in oligodendrocytes JNK activity has been shown to increase as PC12 cells differentiate (Eilers et al, 1998) and to remain elevated after axotomy of adult dorsal root ganglion neurons (Kenney and Kocsis, 1998). Similarly, cerebellar granule neurons exhibit a high basal level of JNK activity (Coffey et al, 2000).…”

GEFT, A Rho Family Guanine Nucleotide Exchange Factor, Regulates Neurite Outgrowth and Dendritic Spine Formation

“…Activation of AP-1, which is a homo-or heterodimer of c-fos and c-jun basic leucine zipper transcription factors, is sufficient to induce neurite outgrowth in PC12 cells (34). In addition, AP-1 binding to its promoter region is dramatically increased immediately following sciatic nerve injury and remains active while neurons are regenerating (35). We found that GEFT is capable of upregulating the activities of both NF-B and AP-1 transcription factors via activation of the Rho family of small GTPases.…”

“…It has been shown that activation of the Rho family of small GTPases leads to the MAPK-dependent activation of a number of transcriptional factors involved in cell proliferation and survival in a diverse number of cell types (33). Specifically, the AP-1 transcription factor, consisting of homo-or heterodimers of c-fos and c-jun, has been shown to be sufficient to induce neurite outgrowth in PC12 cells (34) and play a role in the initial regeneration of neurons after severe injury (35). In addition, the NF-B signaling cascade has been found to be important for both neurite outgrowth and neuron survival (36).…”

c-Jun mediates axotomy-induced dopamine neuron death in vivo

“…Of the signaling pathways associated with neuronal death, a role for the stress-activated protein kinase͞c-Jun N-terminal kinase (SAPK͞JNK) signaling pathway has been implicated in nerve injury (4,5). In this regard, correlative studies have described increased expression of c-Jun and JNK activity after axotomy (6)(7)(8).…”