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Review
. 2013 Jul;14(7):605-14.
doi: 10.1038/embor.2013.64. Epub 2013 May 17.

The DLK Signalling Pathway--A Double-Edged Sword in Neural Development and Regeneration

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Free PMC article
Review

The DLK Signalling Pathway--A Double-Edged Sword in Neural Development and Regeneration

Andrea Tedeschi et al. EMBO Rep. .
Free PMC article

Abstract

Dual leucine zipper kinase (DLK), a mitogen-activated protein kinase kinase kinase, controls axon growth, apoptosis and neuron degeneration during neural development, as well as neurodegeneration after various insults to the adult nervous system. Interestingly, recent studies have also highlighted a role of DLK in promoting axon regeneration in diverse model systems. Invertebrates and vertebrates, cold- and warm-blooded animals, as well as central and peripheral mammalian nervous systems all differ in their ability to regenerate injured axons. Here, we discuss how DLK-dependent signalling regulates apparently contradictory functions during neural development and regeneration in different species. In addition, we outline strategies to fine-tune DLK function, either alone or together with other approaches, to promote axon regeneration in the adult mammalian central nervous system.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
DLK pathways controlling contradictory responses in mammalian neurons. Under certain circumstances, DLK initiates a coordinated sequence of phosphorylation events culminating in the activation of JNK activity. On activation, JNK can phosphorylate various intracellular targets. Interaction with JIPs directs JNK activity towards specific neuronal responses. ATF2/3, activating transcription factor 2/3; CP, cortical plate; DCX, doublecortin; DLK, dual leucine zipper kinase; IZ, intermediate zone; JIP, JNK-interacting protein; JNK, c-Jun amino-terminal kinase; Klf6, Kruppel-like factor 6; MAP1b/2c, microtubule associated protein 1b/2c; MAP2K4/7, mitogen-activated protein kinase kinase 4/7; SCG10, superior cervical ganglion 10; Sprr1a, small proline-rich protein 1A; STAT3, signal transducer and activator of transcription 3; VZ, ventricular zone.
Figure 2
Figure 2
Two MAPK pathways promoting axon regeneration in Caenorhabditis elegans. Injury signals including Ca2+ influx trigger activation of DLK-1 and the DLK-1–MKK-4–PMK-3 pathway. In parallel to the DLK-1 pathway, the MLK-1–MEK-1–KGB-1 pathway is also activated. Whilst DLK-1 can activate both MKK-4 and MEK-1, MLK-1 can only activate MEK-1. CEBP-1, CCAAT/enhancer-binding protein 1; DLK-1, dual leucine zipper kinase 1; JNK, c-Jun amino-terminal kinase; MAPK, mitogen activated protein kinase; MAP2K, mitogen-activated protein kinase kinase; MAP3K, mitogen-activated protein kinase kinase kinase; MKK-4, MAP kinase kinase 4; RPM-1, regulator of presynaptic morphology 1.
Figure 3
Figure 3
Retrograde transport of injury-activated signals. After peripheral nerve lesion, locally activated regulators are retrogradely transported from the site of injury back to the mouse DRG cell body. Absence of DLK prevents the correct translocation of pro-regenerative signals including phospho-STAT3 and c-Jun needed to activate the intrinsic regeneration programme. p-c-Jun, phosphorylated c-Jun; DRG, dorsal root ganglion; DLK, dual leucine zipper kinase; GM, grey matter; JIP3, JNK-interacting protein 3; PNL, peripheral nerve lesion; STAT3, signal transducer and activator of transcription 3; WT, wild-type; WM, white matter.
None
Andrea Tedeschi & Frank Bradke

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