Combined Genetic Attenuation of Myelin and Semaphorin-Mediated Growth Inhibition Is Insufficient to Promote Serotonergic Axon Regeneration

The Journal of Neuroscience, 2010 · DOI: 10.1523/JNEUROSCI.2269-10.2010 · Published: August 11, 2010

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

After spinal cord injuries, substances that inhibit axon growth from myelin and scar tissue are thought to be major obstacles to axon regeneration. This study investigates whether removing multiple inhibitors can promote regeneration. The researchers tested whether removing multiple myelin inhibitors (Nogo, MAG, and NgR1) or Semaphorin inhibitors (PlexinA3 and PlexinA4) could help serotonergic axons regenerate after a complete spinal cord injury in mice. The study found that removing these inhibitors, even in combination, did not significantly improve axon regeneration after a complete spinal cord injury. This suggests other factors are involved in preventing regeneration.

Study Duration

6 Weeks

Participants

Mice deficient in Nogo/MAG/NgR1, PlexinA3/PlexinA4, and NgR1

Evidence Level

Not specified

Key Findings

1
Deleting Nogo, MAG, and NgR1 (three myelin inhibitors) did not enhance serotonergic axon regeneration after complete spinal cord transection.
2
Deleting PlexinA3 and PlexinA4 (Semaphorin receptors), alone or with NgR1, did not promote regeneration of serotonergic or corticospinal axons after complete spinal cord transection.
3
Some axons were able to traverse the injury site through GFAP-negative tissue bridges, suggesting that GFAP-positive areas are particularly inhibitory.

Research Summary

This study investigates the potential of genetically attenuating myelin and Semaphorin-mediated inhibition to promote axon regeneration after spinal cord injury. The research focused on serotonergic and corticospinal axon regeneration in mice deficient in key myelin inhibitors (Nogo, MAG, NgR1) and Semaphorin receptors (PlexinA3, PlexinA4). The findings indicate that neither attenuating myelin-mediated inhibition nor combining it with Semaphorin inhibition is sufficient to promote significant axon regeneration after a complete spinal cord transection.

Practical Implications

Therapeutic Limitations

Targeting myelin-derived and Semaphorin-mediated inhibitory molecules may not be sufficient as a primary strategy for treating spinal cord injury and promoting axon regeneration.

Alternative Targets

Further research should explore other inhibitory molecules and growth-promoting factors to enhance axon regeneration after spinal cord injury.

Microenvironment Matters

The inhibitory nature of GFAP-positive areas and the potentially permissive nature of GFAP-negative bridges suggest that modulating the injury microenvironment could be a viable therapeutic strategy.

Study Limitations

1
The study focused on complete spinal cord transection, which may not fully represent other types of spinal cord injuries.
2
The research utilized genetic deletion of specific molecules, which may not fully replicate the effects of pharmacological interventions.
3
The study was conducted in mice, and the findings may not directly translate to humans due to differences in the CNS environment and regenerative capacity.

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