UTX/KDM6A deletion promotes the recovery of spinal cord injury by epigenetically triggering intrinsic neural regeneration

Molecular Therapy: Methods & Clinical Development, 2021 · DOI: https://doi.org/10.1016/j.omtm.2020.12.004 · Published: March 1, 2021

Spinal Cord Injury Regenerative Medicine Genetics

Simple Explanation

This study investigates how spinal cord injuries (SCI) affect nerve regeneration. It focuses on the epigenetic regulation of axonal regeneration post-SCI, specifically the role of UTX/miR-24/NeuroD1. The researchers found that UTX, an epigenetic regulator, increases after SCI and inhibits axon regeneration. Downregulation of UTX remarkably promoted axonal regeneration. They also found that miR-24, regulated by UTX, inhibits axonal regeneration by negatively regulating NeuroD1 expression, which affects microtubule stability. Deleting UTX in vivo promoted axonal regeneration and functional recovery post-SCI.

Study Duration

8 Weeks

Participants

Adult female UTXﬂox/ﬂox mice

Evidence Level

Not specified

Key Findings

1
UTX expression is significantly increased post-SCI and represses axonal regeneration in vitro.
2
miR-24 is upregulated post-SCI, positively regulated by UTX, and inhibits axonal regeneration by impairing microtubule stability.
3
UTX deletion in vivo prominently promoted axonal regeneration and improved functional recovery post-SCI, and silencing NeuroD1 restored UTX function.

Research Summary

The study elucidates the role of the epigenetic regulatory network involving UTX/miR-24/NeuroD1 in axonal regeneration and functional recovery in mice following SCI. UTX is identified as an intrinsic inhibitor of axonal regrowth in vitro, while miR-24, upregulated post-SCI, inhibits axon regeneration by impairing microtubule stability. UTX deletion in neurons within the lesion improves recovery of spinal function post-SCI in a NeuroD1-dependent manner, facilitating axonal regeneration by stabilizing axonal microtubules in vivo.

Practical Implications

Therapeutic Target

UTX could be a potential therapeutic target in SCI.

Epigenetic Regulation

Epigenetic regulation of NeuroD1 by UTX/miR-24 plays a crucial role in axonal regeneration.

Microtubule Stability

Enhancing microtubule stability through NeuroD1 activation promotes axonal regeneration.

Study Limitations

1
The mechanism by which NeuroD1 affects microtubule stability remains to be further studied.
2
The study focuses on female mice only.
3
Limited investigation into the specific pathways through which NeuroD1 regulates microtubule stabilization in neurons.

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