Mechanisms of Axon Growth and Regeneration: Moving between Development and Disease

The Journal of Neuroscience, 2022 · DOI: https://doi.org/10.1523/JNEUROSCI.1131-22.2022 · Published: November 9, 2022

Simple Explanation

During development, neurons excel at growing axons to connect through synapses. The study investigates how these developmental mechanisms can be reactivated in the adult nervous system to induce axon regeneration after injuries like spinal cord injury. The research explores the balance between growth and growth restraint during neuronal polarization, identifying key molecules and processes involved in initiating and restraining axon growth, such as microtubule stabilization and actin dynamics. The study suggests that synaptic transmission and axon growth may be mutually exclusive processes. Inhibiting synaptic transmission might promote axon regeneration, offering potential therapeutic avenues for spinal cord injury and stroke.

Study Duration

Not specified

Participants

Mouse models, DRG neurons, hippocampal neurons, in vitro cell cultures, EMSCI network patient data

Evidence Level

Not specified

Key Findings

1
Microtubule stabilization and actin dynamics are critical for axon growth and regeneration. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury.
2
The Rho-GTPase RhoA, acting through Myosin II, compacts actin, inhibiting microtubule protrusion and axon regeneration. Inactivation of RhoA in neurons promotes axon regeneration.
3
Voltage-gated calcium channel subunit α2δ2 (Cacna2d2) and vesicle priming machinery proteins like Munc13 act as intrinsic growth inhibitors in mature neurons, suppressing axon regeneration. Blocking these inhibitors promotes regeneration.

Research Summary

The study explores the mechanisms of axon growth and regeneration, focusing on reactivating developmental processes in the adult CNS to overcome regeneration failure after injury. It highlights the balance between growth and growth restraint during neuronal polarization. Key findings include the roles of microtubule stabilization, actin dynamics, and RhoA signaling in regulating axon growth and regeneration. Epothilone B reduces fibrotic scarring and CSPGs, and increases regrowth of serotonergic axons. The research identifies intrinsic growth inhibitors, such as Cacna2d2 and Munc13, that suppress axon regeneration in mature neurons. Blocking these inhibitors, or dampening synaptic transmission, shows promise for promoting regeneration and functional recovery after spinal cord injury and stroke.

Practical Implications

Therapeutic Targeting of Microtubules

Drugs like epothilones can be used to stabilize microtubules, reduce scarring, and promote axon regeneration after spinal cord injury.

Modulation of RhoA Signaling

Neuron-specific inactivation of RhoA or manipulation of its downstream effectors may be a promising approach for promoting axon regeneration.

Inhibition of Synaptic Transmission

Drugs that dampen synaptic transmission, such as baclofen and gabapentinoids, may induce axon regeneration and functional recovery after CNS injuries.

Study Limitations

1
Much of the knowledge relies on 2D substrates rather than 3D or in vivo models.
2
The precise mechanisms of how axons grow (amoeboid movement, substrate-dependent differences) are still fragmentary.
3
The roles of different neuron parts in regulating concerted growth need further exploration (less 'growth-cone-centric' view).

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