Facilitating axon regeneration in the injured central nervous system remains a challenging task. RAF-MAP2K signaling plays a key role in axon elongation during nervous system development. Here, we show that conditional expression of a constitutively kinase-activated BRAF in mature corticospinal neurons elicited the expression of a set of transcription factors previously implicated in the regeneration of zebrafish retinal ganglion cell axons and promoted regeneration and sprouting of corticospinal tract (CST) axons after spinal cord injury in mice. Newly sprouting axon collaterals formed synaptic connections with spinal interneurons, resulting in improved recovery of motor function. Noninvasive suprathreshold high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) activated the BRAF canonical downstream effectors MAP2K1/2 and modulated the expression of a set of regeneration-related transcription factors in a pattern consistent with that induced by BRAF activation. HF-rTMS enabled CST axon regeneration and sprouting, which was abolished in MAP2K1/2 conditional null mice. These data collectively demonstrate a central role of MAP2K signaling in augmenting the growth capacity of mature corticospinal neurons and suggest that HF-rTMS might have potential for treating spinal cord injury by modulating MAP2K signaling.

Facilitating axon regeneration in the injured central nervous system remains a challenging task. RAF - MEK signaling plays an important role in axon elongation during nervous system development. Here we show that activation of B-RAF in mature corticospinal neurons elicited the expression of a discrete set of transcription factors previously implicated in the regeneration of zebrafish optic nerve axons. Genetic activation of B-RAF - MEK signaling promoted robust regeneration and sprouting of corticospinal tract axons after injury. Newly sprouting axon collaterals formed synaptic connections with spinal interneurons, correlating with the recovery of skilled motor function. Seeking a non-invasive way to stimulate axon regeneration, we found that suprathreshold high-frequency repetitive transcranial magnetic stimulation activates the B-RAF canonical effectors MEK1/2 and requires MEK1/2 activity to promote corticospinal axon regeneration and sprouting after injury. These data demonstrate a central role of neuron-intrinsic RAF - MEK signaling in enhancing the growth capacity of mature corticospinal neurons and propose HF-rTMS as a potential therapy for spinal cord injury.