Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration

B-RAF activation in mature corticospinal neurons upregulated a discrete set of transcription factors overlapping with a set induced early in axotomized zebrafish retina ganglion cells which can fully regenerate their axons. Conditional genetic activation of B-RAF promoted robust regeneration and sprouting of corticospinal tract axons after experimental spinal cord injury. Newly sprouting axon collaterals formed synaptic connections, correlating with recovery of skilled motor function. We also found that non-invasive suprathreshold high-frequency repetitive transcranial magnetic stimulation activates the RAF effector MEK and promotes regeneration and sprouting of corticospinal tract axons, dependent on MEK signaling. Our findings demonstrate a central role of neuron-intrinsic RAF–MEK signaling in enhancing the growth capacity of mature corticospinal neurons and propose transcranial magnetic stimulation as a potential therapy for spinal cord injury. Overall design: Comparison of expression profiles induced in mature fezf2-positive corticospinal neurons by conditional expression of constitutively-active B-RAF (V600E point mutation) or by conditional deletion of PTEN, with littermate controls.