The transcription factor combination MEF2 and KLF7 promotes axonal sprouting in the injured spinal cord with functional improvement and regeneration-associated gene expression

Molecular Neurodegeneration, 2025 · DOI: https://doi.org/10.1186/s13024-025-00805-4 · Published: January 23, 2025

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

After a spinal cord injury, nerve cells in the central nervous system often fail to regrow. This study explores how to encourage nerve regeneration by introducing specific proteins called transcription factors (TFs). These TFs can activate genes associated with nerve regeneration. The researchers identified nine candidate TFs and tested different combinations to see which ones best promoted nerve growth in a lab setting. They found that the combination of ATF3, KLF7, and MEF2 was particularly effective. When tested in rats with spinal cord injuries, the combination of KLF7 and MEF2 led to improved nerve sprouting and some functional recovery. Further analysis suggested that this combination struck a better balance than others, avoiding the activation of cell death pathways that can hinder regeneration.

Study Duration

12 weeks

Participants

Female Wistar rats (9–12 weeks old)

Evidence Level

Not specified

Key Findings

1
Promoter analysis identified ATF3, Jun, CEBPD, KLF7, MEF2, SMAD1, SOX11, STAT3 and SRF as candidate RAG-activating TFs.
2
In vitro screening identified two TF combinations, KLF7/MEF2 and ATF3/KLF7/MEF2, that had potent neurite-growth promoting activity, the latter being the more powerful.
3
In vivo, KLF7/MEF2, but not ATF3/KLF7/MEF2 or KLF7 or MEF2 alone, promoted axonal sprouting into the dorsal column lesion site and led to improved functional recovery.

Research Summary

This study aimed to identify transcription factor (TF) combinations that could activate regeneration-associated genes (RAGs) and promote axon regeneration after spinal cord injury. Through in vitro screening, the combination of ATF3/KLF7/MEF2 was found to be highly effective at promoting axon growth. However, in vivo experiments revealed that KLF7/MEF2 was the most effective combination, inducing axonal sprouting and functional recovery. Gene expression profiling indicated that KLF7/MEF2's superiority might be due to its partial induction of the RAG program combined with a lack of induction of apoptosis machinery, which occurred in other combinations.

Practical Implications

Therapeutic Potential

KLF7/MEF2 combination shows promise as a therapeutic target for promoting axon regeneration and functional recovery after spinal cord injury.

Understanding RAG Activation

The study provides insights into the complex transcriptional regulation of axon regeneration and the importance of balancing RAG activation with apoptosis.

Optimizing TF Combinations

Further research should focus on optimizing TF combinations and delivery methods to maximize their regenerative potential in vivo.

Study Limitations

1
The study used only female rats, which may limit the generalizability of the findings.
2
The in vitro screening was performed using F11 cells, which may not fully represent the in vivo environment of DRG neurons.
3
MEF2 showed little transcriptional activity in vivo, which could be due to the constitutive repression of MEF2 activity.

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