A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord

The Journal of Neuroscience, 2022 · DOI: https://doi.org/10.1523/JNEUROSCI.2495-21.2022 · Published: May 4, 2022

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This research investigates how two protein kinases, DLK and LZK, affect the ability of nerve fibers (axons) to repair themselves after a spinal cord injury in mammals. The study found that both DLK and LZK are crucial for axons to regenerate and sprout, which are two ways the nervous system can recover after injury. These kinases not only help injured neurons regenerate but also assist uninjured neurons in sprouting new connections, suggesting a broader role in CNS repair than previously thought.

Study Duration

8 weeks

Participants

Mice (both sexes)

Evidence Level

Level 2: Experimental study using genetically modified mice

Key Findings

1
The inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons.
2
Deleting DLK and LZK does not interfere with PTEN/mTOR signaling, indicating that injury signaling and regenerative competence are independently controlled.
3
Co-deletion of DLK and LZK suppressed spontaneous CST sprouting to below wild-type levels.

Research Summary

This study demonstrates the critical role of neuronal DLK and LZK in axonal repair including both regeneration and sprouting in the mammalian spinal cord. DLK/LZK-dependent injury signaling and PTEN/mTOR-dependent regenerative competence are likely independently controlled parallel processes, both of which are required for regeneration. The same signaling pathway such as the one involving DLK and LZK can function simultaneously in multiple cell types in the multicellular response to CNS injury.

Practical Implications

Therapeutic Targets

DLK and LZK are potential targets to promote repair and recovery after spinal cord injury.

Multicellular Approach

Therapeutic strategies should consider the multicellular function of DLK/LZK signaling in both neurons and glia.

Combination Therapies

Combining interventions that enhance regenerative competence (e.g., PTEN deletion) with those that promote injury signaling (DLK/LZK modulation) may be synergistic.

Study Limitations

1
The study primarily used the CST as the experimental system, limiting generalizability to other axonal tracts.
2
AAV2 vectors predominantly infect neurons; a small effect through infection of brain astrocytes around the AAV injection site cannot be excluded.
3
The study focused on regeneration and sprouting; the role of DLK and LZK in cell death was not directly assessed.

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