Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation

PNAS, 2009 · DOI: 10.1073/pnas.0810624106 · Published: April 28, 2009

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

The corticospinal tract, crucial for voluntary movement in primates, doesn't regenerate well after injury. This study explores enhancing intrinsic neuronal growth to promote regeneration. Lentiviral vectors were used to deliver the BDNF receptor trkB to corticospinal motor neurons. This led to corticospinal axon regeneration into lesion sites expressing BDNF. The regeneration was dependent on Erk signaling. When this signaling was blocked, regeneration did not occur, suggesting that activating Erk signaling can induce corticospinal tract regeneration.

Study Duration

Not specified

Participants

Rats

Evidence Level

Level 2; Experimental Study

Key Findings

1
Overexpression of trkB in layer V motor cortex in vivo induces axonal regeneration after subcortical axotomy.
2
Regenerating corticospinal axons were detected in BDNF-secreting subcortical lesion sites, and these axons expressed both copGFP (indicating trkB infection) and eGFP (indicating retrograde infection from the spinal cord).
3
trkB tyrosine 515 phosphorylation, which is essential for Erk activation, is critical for neurite outgrowth in vitro and axonal regeneration in vivo.

Research Summary

The study investigates methods to induce regeneration of corticospinal axons, which are crucial for motor function but typically do not regenerate after injury. The researchers hypothesized that enhancing intrinsic neuronal growth mechanisms would enable regeneration. Lentiviral vectors were used to overexpress the BDNF receptor trkB in corticospinal motor neurons. This resulted in corticospinal axon regeneration into subcortical lesion sites expressing BDNF. Regeneration was dependent on trkB-mediated Erk activation. The findings demonstrate that corticospinal axon regeneration can be induced by modulating the intrinsic neuronal growth state and that canonical signaling of the Erk/MEK pathway through trkB tyrosine 515 phosphorylation is essential for this regenerative effect.

Practical Implications

Therapeutic Target

Enhancing Erk/MEK signaling may be a viable therapeutic strategy for promoting corticospinal axon regeneration after CNS injury.

Delivery Methods

Lentiviral vectors can be used to deliver growth-inducing neurotrophin receptors to the axonal compartment, promoting regeneration of previously refractory neuronal systems.

Combination Therapies

Eliciting corticospinal regeneration into lesions located at more caudal levels of the neuraxis, including the spinal cord, it will be necessary to induce trafficking of the trkB receptor further down the distal axonal compartment.

Study Limitations

1
The study used a subcortical lesion model, which may not fully represent spinal cord injuries.
2
Further research is needed to induce trafficking of the trkB receptor further down the distal axonal compartment to promote regeneration into lesions located at more caudal levels of the neuraxis, including the spinal cord.
3
Eventual functional bridging of axons beyond a lesion site will likely require additional interventions, including trophic factor gradients extending beyond the lesion site (46, 47), modification of the inhibitory environment (9, 10, 48), or both.

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