Distinct Roles of c-Jun N-Terminal Kinase Isoforms in Neurite Initiation and Elongation during Axonal Regeneration

Abstract

c-Jun N-terminal kinases (JNKs) (comprising JNK1-3 isoforms) are members of the MAPK (mitogen-activated protein kinase) family, activated in response to various stimuli including growth factors and inflammatory cytokines. Their activation is facilitated by scaffold proteins, notably JNK-interacting protein-1 (JIP1). Originally considered to be mediators of neuronal degeneration in response to stress and injury, recent studies support a role of JNKs in early stages of neurite outgrowth, including adult axonal regeneration. However, the function of individual JNK isoforms, and their potential effector molecules, remained unknown. Here, we analyzed the role of JNK signaling during axonal regeneration from adult mouse dorsal root ganglion (DRG) neurons, combining pharmacological JNK inhibition and mice deficient for each JNK isoform and for JIP1. We demonstrate that neuritogenesis is delayed by lack of JNK2 and JNK3, but not JNK1. JNK signaling is further required for sustained neurite elongation, as pharmacological JNK inhibition resulted in massive neurite retraction. This function relies on JNK1 and JNK2. Neurite regeneration of jip1 Ϫ/Ϫ DRG neurons is affected at both initiation and extension stages. Interestingly, activated JNKs (phospho-JNKs), as well as JIP1, are also present in the cytoplasm of sprouting or regenerating axons, suggesting a local action on cytoskeleton proteins. Indeed, we have shown that JNK1 and JNK2 regulate the phosphorylation state of microtubule-associated protein MAP1B, whose role in axonal regeneration was previously characterized. Moreover, lack of MAP1B prevents neurite retraction induced by JNK inhibition. Thus, signaling by individual JNKs is differentially implicated in the reorganization of the cytoskeleton, and neurite regeneration.

JNK regulates FoxO-dependent autophagy in neurons

“…The JNK signaling pathway is implicated in microtubule stabilization and the regulation of axodendritic morphology (Coffey et al 2000;Chang et al 2003;Bjorkblom et al 2005;Tararuk et al 2006;Barnat et al 2010). JNK inhibition may therefore increase microtubule instability and cause neurite retraction.…”

“…JNK-induced phosphorylation of microtubule-associated proteinsincluding Doublecortin (Gdalyahu et al 2004), MAP1B (Chang et al 2003;Barnat et al 2010), MAP2 (Chang et al 2003), the stathmin protein family of microtubuledestabilizing proteins (Tararuk et al 2006), and Tau (Yoshida et al 2004)-may influence microtubule function. This action of JNK is important for neurite formation.…”

“…This action of JNK is important for neurite formation. Thus, JNK contributes to bone morphogenic proteinstimulated dendrite formation (Podkowa et al 2010), the structure of dendritic architecture (Coffey et al 2000;Bjorkblom et al 2005), axodendritic length (Tararuk et al 2006), and axonal regeneration (Barnat et al 2010). Moreover, JNK can regulate kinesin-mediated fast axonal transport on microtubules (Morfini et al 2006(Morfini et al , 2009) and contributes to the regulation of synaptic plasticity (Chen et al 2005;Zhu et al 2005;Li et al 2007; Thomas et al 2008).…”

Axon Formation in Neocortical Neurons Depends on Stage-Specific Regulation of Microtubule Stability by the Dual Leucine Zipper Kinase–c-Jun N-Terminal Kinase Pathway

“…More recently, the JNK-related genes, JNK1, JNK2, and JNK3, were also shown to contribute to axon regeneration in cultured dorsal root ganglion (DRG) neurons (Barnat et al, 2010). Evaluation of the direct contribution of JNK to axon formation, in vivo, has been hampered by the presence of these three JNK-related genes and their critical functions at early stages of embryogenesis (Kuan et al, 1999).…”

Regulation of axon growth by the JIP1-AKT axis

“…Furthermore, the manipulation of the JIP1-AKT axis could represent a potential route for promoting nerve regeneration. There is already evidence that JIP1 promotes regeneration of adult mouse dorsal root ganglion neurons (Barnat et al, 2010) and a number of studies have proposed a role for AKT-mediated signalling in axonal regeneration (Namikawa et al, 2000;Kim et al, 2011;Song et al, 2012).…”