News & Impact

You are here

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

Journal Article
Francesco Boato, Xiaofei Guan, Yanjie Zhu, Youngjae Ryu, Mariel Voutounou, Christopher Rynne, Chase R Freschlin, Paul Zumbo, Doron Betel, Katie Matho, Sergey N Makarov, Zhuhao Wu, Young-Jin Son, Aapo Nummenmaa, Josh Z Huang, Dylan J Edwards, Jian Zhong
Year Published: 
Sci Transl Med . 2023 Jan 4;15(677):eabq6885. doi: 10.1126/scitranslmed.abq6885. Epub 2023 Jan 4.
PMID: 36599003 | DOI: 10.1126/scitranslmed.abq6885
Full Text on Atypon


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.

Research Methods