Neuronal deletion of GSK3β increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2

BMC Biology, 2014 · DOI: 10.1186/1741-7007-12-47 · Published: June 12, 2014

Regenerative Medicine Neurology Genetics

Simple Explanation

This study investigates how nerve cells regrow after spinal cord injury. Researchers found that a protein called GSK3β slows down the growth of tiny tubes (microtubules) inside the nerve cell's growth cone. When GSK3β is removed or its activity is reduced, these microtubules grow faster, helping the nerve cell to regrow more effectively through scar tissue. Another protein, CRMP-2, works with GSK3β to control this process. By inactivating GSK3β, CRMP-2 helps speed up microtubule growth and improve nerve regeneration.

Study Duration

5 weeks post-injury

Participants

Rats and mice with spinal cord injury

Evidence Level

Not specified

Key Findings

1
Decreased GSK3β activity and increased microtubule growth speed are present in conditioned neurons with high regenerative capacity.
2
Neuronal deletion of GSK3β leads to increased growth cone microtubule growth speed and promoted axon regeneration after spinal cord injury.
3
Inactivation of the GSK3β-CRMP-2 pathway enhances axon regeneration through the glial scar.

Research Summary

The study demonstrates that increased microtubule dynamics in the growth cone are associated with enhanced axonal growth, particularly after a conditioning lesion. GSK3β, a kinase regulating microtubule-interacting proteins, plays a crucial role in this process. Decreasing GSK3β activity, specifically through reduced Tyr216 phosphorylation, promotes axonal regeneration. The effects of GSK3β are mediated by CRMP-2, a downstream target that controls microtubule dynamics in the growth cone. Inactivation of the GSK3β-CRMP-2 pathway is essential for overcoming growth repression by CNS inhibitors.

Practical Implications

Therapeutic Target Identification

Modulating CRMP-2 activity could be a promising therapeutic strategy to induce axonal regeneration in spinal cord injury and other conditions requiring nerve repair.

Understanding Axon Regeneration

A precise control of microtubule dynamics, specifically in the growth cone, is required to optimize axon regrowth. The GSK3β-CRMP-2 pathway offers a target to control this dynamic.

Drug Development

Developing CRMP-2-specific drugs, capable of modulating its activity, should be further explored in SCI and other conditions where axonal regeneration needs to be promoted.

Study Limitations

1
The study acknowledges that the conditioning lesion effect is complex and involves multiple components, suggesting that other pathways besides the GSK3β-CRMP-2 pathway might also contribute to this effect.
2
The efficiency of nucleofection and transduction in DRG neuron cultures is low, precluding a straightforward comparison between endogenous and overexpressed protein levels.
3
Although the study demonstrates that total ablation of GSK3β increases axonal regeneration, it remains unclear whether a GSK3β gradient is required to enable axonal growth under other conditions.

Your Feedback

Was this summary helpful?

Back to Regenerative Medicine