Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human

Brain, 2022 · DOI: https://doi.org/10.1093/brain/awab317 · Published: January 4, 2022

Neurology Regenerative Medicine & Stem Cells

Simple Explanation

This study investigates the role of Celsr2, a protein highly expressed in spinal motor neurons, in axon regeneration. The research finds that inactivating Celsr2 promotes axon regeneration and fasciculation (bundling) in both mouse and human motor neurons. The study suggests Celsr2 negatively regulates motor axon regeneration, making it a potential target for therapies to improve neural repair after injuries.

Study Duration

56 days

Participants

Mice (Celsr2 cKO and Celsr2f/–), human embryos

Evidence Level

Not specified

Key Findings

1
Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants and cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones.
2
Mice with Celsr2 conditional knockout in spinal motor neurons show improved axon regeneration and functional forelimb locomotor recovery after branchial plexus injury.
3
Knockdown of CELSR2 in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth.

Research Summary

The study demonstrates that Celsr2, highly expressed in spinal motor neurons, inhibits axon regeneration. Inactivating Celsr2 in mice and human motor neurons promotes axon growth, fasciculation, and functional recovery after injury. Celsr2 downregulation is associated with increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun, suggesting a mechanistic pathway.

Practical Implications

Therapeutic Target

Celsr2 could be a potential therapeutic target for promoting neural repair after spinal cord injuries or brachial plexus injuries.

Drug Development

Development of drugs that inhibit Celsr2 function might enhance axon regeneration and improve functional outcomes in patients with nerve injuries.

Combination Therapies

Combining Celsr2 inhibition with other regenerative strategies could lead to more effective treatments for nerve damage.

Study Limitations

1
The precise mechanisms by which Celsr2 regulates Rac1/Cdc42 signaling require further investigation.
2
The study focuses primarily on motor neurons; the role of Celsr2 in other neuronal types and glial cells needs to be explored.
3
Long-term effects of Celsr2 inactivation on neural function and potential side effects need to be assessed.

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