KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

Scientific Reports, 2018 · DOI: 10.1038/s41598-018-31101-5 · Published: August 10, 2018

Regenerative Medicine Neurology Genetics

Simple Explanation

This study investigates how to promote axon regeneration in the central nervous system (CNS) after injury, focusing on KLF6, a transcription factor that can influence axon regeneration. The researchers found that KLF6 promotes axon regeneration in corticospinal tract neurons after spinal cord injury. They identified genes whose expression changed with KLF6, related to axon extension. The study also found that KLF6 interacts with another transcription factor, STAT3, and together they synergistically increase neurite growth. This suggests potential interventions to promote CNS regeneration.

Study Duration

12 weeks

Participants

>8wks age, 20–22 g adult female C57/Bl6 mice, postnatal Sprague Dawley rat pups

Evidence Level

Not specified

Key Findings

1
Forced expression of KLF6 promotes axon regeneration by corticospinal tract neurons in the injured spinal cord.
2
KLF6 and STAT3 co-expression yields a synergistic elevation of neurite growth in vitro.
3
KLF6 and STAT3 show high co-occupancy on regulatory DNA in regeneration-relevant gene networks.

Research Summary

The study demonstrates that forced expression of KLF6 promotes axon regeneration in corticospinal tract neurons after spinal cord injury. RNA sequencing identified genes whose expression changed upon forced KLF6 expression in vitro, including genes relevant to axon extension. KLF6 and STAT3 co-expression synergistically elevated neurite growth in vitro, and they showed high co-occupancy on regulatory DNA in regeneration-relevant gene networks.

Practical Implications

Therapeutic target

KLF6 is an effective pro-regenerative TF that does not depend on an artificial VP16 transcription domain, making it a better candidate for eventual translation.

Combination therapy

Combined KLF6/STAT3 activity can be a first step in reconstructing transcriptional networks.

Further research

Experiments to test combined expression of KLF6/STAT3 in CST neurons to produce improvements in axon regeneration or functional recovery above the level of KLF6 alone.

Study Limitations

1
KLF6 treatment had no effect on forelimb placement in the horizontal ladder task at any time point post-injury.
2
Growth promotion by KLF6 may require changes in the abundance of multiple, functionally interacting genes.
3
Co-expression with KLF4 has been previously tested.

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