Promotion of corticospinal tract growth by KLF6 requires an injury stimulus and occurs within four weeks of treatment

Axons in the corticospinal tract (CST) display a limited capacity for compensatory sprouting after partial spinal injuries, potentially limiting functional recovery. Forced expression of a developmentally expressed transcription factor, Kriippel-like factor 6 (KLF6), enhances axon sprouting by adult CST neurons. Here, using a pyramidotomy model of injury in adult mice, we confirm KLF6's pro-sprouting properties in spared corticospinal tract neurons and show that this effect depends on an injury stimulus. In addition, we probed the time course of KLF6-triggered sprouting of CST axons and demonstrate a significant enhancement of growth within four weeks of treatment. Finally, we tested whether KLF6-induced sprouting was accompanied by improvements in forelimb function, either singly or when combined with intensive rehabilitation. We found that regardless of rehabilitative training, and despite robust cross-midline sprouting by corticospinal tract axons, treatment with KLF6 produced no significant improvement in forelimb function on either a modified ladder-crossing task or a pellet-retrieval task. These data clarify important details of KLF6's pro-growth properties and indicate that additional interventions or further optimization will be needed to translate this improvement in axon growth into functional gains.

Automated summary

Forced expression of the transcription factor KLF6 enhanced axon sprouting in adult CST neurons after spinal injuries, but this effect required an injury stimulus and showed significant growth enhancement within four weeks. However, treatment with KLF6 did not lead to significant improvements in forelimb function, despite robust cross-midline sprouting by CST axons. Additional interventions or further optimization may be needed to translate the improvements in axon growth into functional gains.