Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis.

Autor:	Huang H; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Jing B; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China. Electronic address: jing_scenery@126.com., Zhu F; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Jiang W; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China., Tang P; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China., Shi L; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Chen H; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Ren G; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Xia S; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Wang L; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Cui Y; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China., Yang Z; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Platero AJ; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Hutchins AP; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China., Chen M; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China., Worley PF; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: pworley1@jhmi.edu., Xiao B; Departments of Neuroscience and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen Key Laboratory for Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China. Electronic address: xiaob@sustech.edu.cn.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Jul 25; Vol. 42 (7), pp. 112801. Date of Electronic Publication: 2023 Jul 17.
DOI:	10.1016/j.celrep.2023.112801
Abstrakt:	How neuronal signaling affects brain myelination remains poorly understood. We show dysregulated neuronal RHEB-mTORC1-DLK1 axis impairs brain myelination. Neuronal Rheb cKO impairs oligodendrocyte differentiation/myelination, with activated neuronal expression of the imprinted gene Dlk1. Neuronal Dlk1 cKO ameliorates myelination deficit in neuronal Rheb cKO mice, indicating that activated neuronal Dlk1 expression contributes to impaired myelination caused by Rheb cKO. The effect of Rheb cKO on Dlk1 expression is mediated by mTORC1; neuronal mTor cKO and Raptor cKO and pharmacological inhibition of mTORC1 recapitulate elevated neuronal Dlk1 expression. We demonstrate that both a secreted form of DLK1 and a membrane-bound DLK1 inhibit the differentiation of cultured oligodendrocyte precursor cells into oligodendrocytes expressing myelin proteins. Finally, neuronal expression of Dlk1 in transgenic mice reduces the formation of mature oligodendrocytes and myelination. This study identifies Dlk1 as an inhibitor of oligodendrocyte myelination and a mechanism linking altered neuronal signaling with oligodendrocyte dysfunction. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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