Extrinsic and intrinsic regulation of axon regeneration at a crossroads

Front. Mol. Neurosci., 2015 · DOI: 10.3389/fnmol.2015.00027 · Published: June 16, 2015

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

The adult mammalian central nervous system (CNS) has a poor ability to regenerate and restore function after injury. The presence of inhibitory factors in the CNS microenvironment contributes to the failure of axons to regenerate. Myelin-associated inhibitors (MAIs) including Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) collapse axonal growth cones and inhibit growth. The deposition of chondroitin sulfate proteoglycans (CSPGs) by reactive astrocytes also presents a formidable barrier to axon regeneration through sites of injury. Targeting these extrinsic inhibitory factors has led to modest improvements in axonal plasticity and functional recovery after CNS injury. The neuron-intrinsic growth state can regulate the sensitivity of the injured axon to extrinsic factors.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
CNS myelin contains myelin-associated inhibitors (MAIs) including Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) that collapse axonal growth cones and inhibit growth.
2
The deposition of chondroitin sulfate proteoglycans (CSPGs) by reactive astrocytes also presents a formidable barrier to axon regeneration through sites of injury.
3
Filbin and colleagues demonstrated that an age-associated decline in neuronal cAMP underlies a gain of sensitivity to myelin-mediated inhibition.

Research Summary

Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need.

Practical Implications

Targeting Myelin-Associated Inhibitors

Development of selective antagonists to neutralize the inhibitory effect of myelin proteins may improve regeneration.

Pharmacological targeting of CSPG receptors

Relieving CSPG-dependent capture of growth cones can improve serotonergic axon sprouting and functional recovery after SCI.

Growth Stimulation

Targeting intracellular growth regulators may drive neuron growth and relieve sensitivity to extrinsic inhibition of growth.

Study Limitations

1
Variable effects of deleting NgR or Nogo, MAG and OMgp in mice on regeneration and recovery.
2
Concerns about oncogenesis with chronic targeting of tumor suppressors.
3
The relative contribution of the receptor-ligand interaction and downstream signaling events to growth cone immobilization remain unclear.

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