Krüppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract

PNAS, 2012 · DOI: 10.1073/pnas.1120684109 · Published: May 8, 2012

Simple Explanation

Axon regeneration in the central nervous system fails due to a decline in the intrinsic ability of CNS projection neurons to extend axons. The KLF family of transcription factors, particularly KLF7, regulates this regenerative potential but is down-regulated developmentally. To enhance KLF7's effect, a chimera with the VP16 transactivation domain was created, improving neuronal expression and growth promotion. This VP16-KLF7 chimera overcame the developmental loss of regenerative ability in cortical slice cultures. Adult corticospinal tract (CST) neurons do not up-regulate KLF7 after axon injury. Overexpression of VP16-KLF7 in vivo promoted both sprouting and regenerative axon growth in the CST of adult mice, offering a means to promote CST axon regeneration.

Study Duration

Not specified

Participants

Adult mice

Evidence Level

Not specified

Key Findings

1
VP16-KLF7 effectively promotes neurite outgrowth and displays enhanced expression compared to wild-type KLF7 in dissociated neurons.
2
Overexpression of VP16-KLF7 in cortical slices mitigates the age-dependent decline in axon growth following injury.
3
In adult mice, VP16-KLF7 overexpression promotes both sprouting and regenerative axon growth within the corticospinal tract following spinal cord injury.

Research Summary

The study addresses the failure of axon regeneration in the CNS due to a developmental decline in the intrinsic ability of neurons to extend axons, focusing on the transcription factor KLF7. To overcome limitations in KLF7 expression, a VP16-KLF7 chimera was created, demonstrating enhanced neuronal expression and growth promotion in vitro and in cortical slice cultures. In vivo experiments showed that VP16-KLF7 overexpression in adult mice promoted sprouting and regenerative axon growth in the corticospinal tract after spinal cord injury, suggesting a potential therapeutic approach.

Practical Implications

Gene Therapy Potential

VP16-KLF7 could be a therapeutic target for promoting axon regeneration after spinal cord injury.

Drug Development

Small molecules that enhance KLF7 activity or mimic its effects could be developed to promote axon regeneration.

Combination Therapies

VP16-KLF7 could be combined with other regenerative strategies, such as neutralizing inhibitory molecules, to enhance axon regeneration and functional recovery.

Study Limitations

1
VP16-KLF7 might activate nonphysiological targets, confounding conclusions regarding endogenous KLF7.
2
The regenerative response evoked by VP16-KLF7 remains incomplete in terms of the percent of neurons that respond to treatment.
3
The study does not fully address whether regenerated axons form functional synapses and lead to behavioral improvements.

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