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

Boato, Francesco, Guan, Xiaofei, Zhu, Yanjie, Ryu, Youngjae, Voutounou, Mariel, Rynne, Christopher, Freschlin, Chase R, Zumbo, Paul, Betel, Doron, Matho, Katie, Makarov, Sergey N, Wu, Zhuhao, Son, Young-Jin, Nummenmaa, Aapo, Huang, Josh Z, Edwards, Dylan J, Zhong, Jian (January 2023) Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration. Science Translational Medicine, 15 (677). eabq6885. ISSN 1946-6234

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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > tissues types and functions > axon bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes organism description > animal > fish bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor organism description > animal > fish > zebrafish
CSHL Authors:	Matho, Katherine Huang, Z. Josh
Communities:	CSHL labs > Huang lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	4 January 2023
Date Deposited:	23 Jan 2023 15:59
Last Modified:	08 Jan 2024 16:56
URI:	https://repository.cshl.edu/id/eprint/40794

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