Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis
Haijiao Huang,
Bo Jing,
Feiyan Zhu,
Wanxiang Jiang,
Ping Tang,
Liyang Shi,
Huiting Chen,
Guoru Ren,
Shiyao Xia,
Luoling Wang,
Yiyuan Cui,
Zhiwen Yang,
Alexander J. Platero,
Andrew P. Hutchins,
Mina Chen,
Paul F. Worley,
Bo Xiao
Affiliations
Haijiao Huang
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
Bo Jing
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; Corresponding author
Feiyan Zhu
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
Wanxiang Jiang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
Ping Tang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
Liyang Shi
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
Huiting Chen
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
Guoru Ren
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
Shiyao Xia
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
Luoling Wang
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
Yiyuan Cui
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
Zhiwen Yang
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
Alexander J. Platero
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Andrew P. Hutchins
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
Mina Chen
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China
Paul F. Worley
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Corresponding author
Bo Xiao
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; Corresponding author
Summary: 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.
