@article{4e7ab3c889294977b9e54b50de02f79f,
title = "Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration",
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.",
author = "Francesco Boato and Xiaofei Guan and Yanjie Zhu and Youngjae Ryu and Mariel Voutounou and Christopher Rynne and Freschlin, {Chase R.} and Paul Zumbo and Doron Betel and Katie Matho and Makarov, {Sergey N.} and Zhuhao Wu and Son, {Young Jin} and Aapo Nummenmaa and Huang, {Josh Z.} and Edwards, {Dylan J.} and Jian Zhong",
note = "Funding Information: We are grateful to F. Nicola, J. Kaiser, and V. Sahni of the Burke Institute for help with RNA-seq analyses; Y. Liu and Z. He from Boston Children{\textquoteright}s Hospital for providing Hi-Ret lentiviruses and sharing expertise in spinal cord surgery; and A. Markus for insightful discussion and help with manuscript preparation. We would also like to thank Y. Todorov and H. Corfitzen from MagVenture for providing information about the TMS coil characteristics. This work was supported by grants from the National Institutes of Health, R01NS099568 (to J.Z.); the New York State Department of Health Spinal Cord Injury Research Board (SCIRB) C33611GG, C33270GG, C34462GG, and C32092GG (all to J.Z.); the Craig H. Neilsen Foundation, 296098 and 546849 (both to J.Z.); and the Wings for Life Research foundation, WFL-US-028/14 (to J.Z.). F.B. was supported by a fellowship from the Goldsmith Research Foundation, and X.G. was supported by a SCIRB fellowship C30863GG. A.N. was supported by the National Institutes of Health R01MH111829, R00EB015445, and P41EB030006. J.Z. also received support from the Burke Foundation. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",
year = "2023",
month = jan,
day = "4",
doi = "10.1126/scitranslmed.abq6885",
language = "English",
volume = "15",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "677",
}