Activation of c-Jun N-terminal kinase is required for neurite outgrowth of dopaminergic neuronal cells

Abstract

Recent studies indicate that activation of stress-activated protein kinases may be implicated in a broad range of biological activities including differentiation. To directly examine whether stress-activated protein kinases are involved in neuronal differentiation, we utilized retinoic acid-induced and spontaneous models of neurite outgrowth in dopaminergic neurons. Here, we show that retinoic acid-induced neurite outgrowth in MN9D dopaminergic neuronal cells was accompanied by activation of c-Jun N-terminal kinase but not p38. Consequently, cotreatment with a specific inhibitor of c-Jun N-terminal kinase or overexpression of c-Jun N-terminal kinase-binding domain of c-Jun N-terminal kinase-interacting protein-1 blocked retinoic acid-induced neurite outgrowth. In primary cultures of dopaminergic neurons, the extent of neurite outgrowth increased spontaneously in a time-dependent manner. When these cultures were treated with a specific inhibitor of c-Jun N-terminal kinase, the total extent of neurites, the primary neurite length and the number of neurites per cell were suppressed significantly. Thus, our data indicate that the c-Jun N-terminal kinase signal seems to play an important role during morphological differentiation in cultured dopaminergic neurons.

Synaptogenesis Regulates Axotomy-Induced Activation of c-Jun-Activator Protein-1 Transcription

“…5). Although others have implicated JNK in growth (Yao et al, 1997;Waetzig and Herdegen, 2003;Eom et al, 2005), our findings suggest that, in a single defined population of sensory neurons, this pathway does not significantly influence neurite growth per se. Other classes of neurons might respond differently.…”

Wnt-3a and Dickkopf-1 Stimulate Neurite Outgrowth in Ewing Tumor Cells via a Frizzled3- and c-Jun N-Terminal Kinase-Dependent Mechanism

“…These results were reinforced when similar data were obtained following siRNA knockdown of JNK1. Others have shown that the activation of JNK is required for neurite outgrowth in dopaminergic (11) and hippocampal (28,32) neurons. Jnk1 Ϫ/Ϫ mice had severe defects in the anterior commissure tract and a progressive loss of microtubules within axons and dendrites (5), demonstrating that JNK1 is required for the maintenance of neuronal microtubules.…”

“…JNK is a well-established downstream effector of Wnt/noncanonical signaling in the convergent extension/planar cell polarity pathway (34). It also has been identified as a key mediator of neurite outgrowth (11,28), specifically functioning in Wnt-7b-dependent, Dvl/Rac-mediated dendritic arborization (32). To examine the potential role of JNK in Wnt-dependent neurite outgrowth, we first sought evidence of the activation of JNK following the exposure of TC-32 cells to Wnt-3a.…”

“…Although the origin of ESFT cells is uncertain, they exhibit neuronal features (4,17,27). Approximately 85% of ESFT tumors result from a specific translocation between chromosomes 11 and 22, t (11,22), that generates EWS-FLI, a fusion protein containing a member of the Ets family of transcription factors (30). Recent microarray data indicate that ESFT cells have expression patterns that resemble those of neuroectoderm and endothelial cells (36) and that EWS-FLI can induce expression of genes typical of a neural crest phenotype (31).…”

Initiating and Growing an Axon

“…Nonetheless, deletion of a single isoform, JNK1, disrupts axon tract maintenance in vivo (Chang et al 2003;Bjorkblom et al 2005). The role of JNKs in axonal polarity and initiation is further supported by many cell culture studies showing that JNK inhibition attenuates neuritogenesis (Leppa et al 1998;Waetzig and Herdegen 2003;Eom et al 2005;Oliva et al 2006;Newbern et al 2007). Numerous lines of evidence suggest this pathway is also important for axonal extension (Leppa et al 1998;Rosso et al 2005;Xiao et al 2006;Ciani and Salinas 2007;Eminel et al 2008).…”