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Updated: Jun 12, 2026
Standardization of a Novel Semi-Automatic Software for Neurite Outgrowth Measurement
Published on: August 9, 2024
Distinct roles of c-Jun N-terminal kinase isoforms in neurite initiation and elongation during axonal regeneration
Monia Barnat1, Hervé Enslen, Friedrich Propst
1Inserm Unité 952, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7224, Paris, France.
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(-/-) 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.
Insights
c-Jun N-terminal kinases (JNKs) are crucial for adult axonal regeneration, with JNK2 and JNK3 essential for neurite outgrowth initiation. JNK1 and JNK2 also prevent neurite retraction by regulating MAP1B phosphorylation.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- c-Jun N-terminal kinases (JNKs), part of the MAPK family, are activated by stimuli like growth factors and cytokines.
- JNKs were historically linked to neuronal degeneration but recent findings suggest roles in neurite outgrowth and axonal regeneration.
- The specific functions of individual JNK isoforms and their downstream effectors in axonal regeneration remained unclear.
Purpose of the Study:
- To investigate the role of JNK signaling in adult axonal regeneration from mouse dorsal root ganglion (DRG) neurons.
- To elucidate the distinct functions of JNK1, JNK2, and JNK3 isoforms, as well as JIP1, in neurite outgrowth and regeneration.
- To identify effector molecules regulated by JNK signaling during axonal regeneration.
Main Methods:
- Pharmacological inhibition of JNK signaling pathways.
- Analysis of JNK isoform-deficient (JNK1, JNK2, JNK3) and JIP1-deficient (jip1(-/-)) mouse models.
- Assessment of neurite outgrowth, initiation, and elongation in dorsal root ganglion (DRG) neurons.
Main Results:
- Neurite outgrowth initiation was delayed in the absence of JNK2 and JNK3, but not JNK1.
- Sustained neurite elongation required JNK1 and JNK2, as JNK inhibition caused significant neurite retraction.
- jip1(-/-) DRG neurons exhibited defects in both neurite initiation and extension.
- Activated JNKs and JIP1 were localized to the cytoplasm of regenerating axons, suggesting local cytoskeletal regulation.
- JNK1 and JNK2 were shown to regulate the phosphorylation of MAP1B, a key protein in axonal regeneration.
- MAP1B deficiency prevented neurite retraction induced by JNK inhibition.
Conclusions:
- Individual JNK isoforms play distinct roles in axonal regeneration.
- JNK signaling, particularly involving JNK1 and JNK2, is essential for maintaining neurite integrity and elongation.
- JNKs, via regulation of MAP1B phosphorylation, contribute to cytoskeletal reorganization necessary for successful axonal regeneration.
- JIP1 is critical for both the initiation and extension phases of neurite regeneration.
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