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

Authors

• 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

Publication/Presentation Date

1-4-2023

Abstract

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.

Volume

15

Issue

677

First Page

6885

Last Page

6885

ISSN

1946-6242

Published In/Presented At

Boato, F., Guan, X., Zhu, Y., Ryu, Y., Voutounou, M., Rynne, C., Freschlin, C. R., Zumbo, P., Betel, D., Matho, K., Makarov, S. N., Wu, Z., Son, Y. J., Nummenmaa, A., Huang, J. Z., Edwards, D. J., & Zhong, J. (2023). Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration. Science translational medicine, 15(677), eabq6885. https://doi.org/10.1126/scitranslmed.abq6885

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

36599003

Department(s)

Administration and Leadership

Document Type

Article