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

doi:10.1016/j.celrep.2023.112801

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

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	112801
Journal	Cell Reports
Volume	42
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2023.112801
State	Published - Jul 25 2023
Externally published	Yes

Keywords

CP: Developmental biology
CP: Neuroscience
DLK1
Raptor
Rheb
hypomyelination
mTORC1
myelination
myelination deficit
neuron-OPC interaction
neuron-glia interaction
oligodendrocyte differentiation

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.112801

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Huang, H., Jing, B., Zhu, F., Jiang, W., Tang, P., Shi, L., Chen, H., Ren, G., Xia, S., Wang, L., Cui, Y., Yang, Z., Platero, A. J., Hutchins, A. P., Chen, M., Worley, P. F., & Xiao, B. (2023). Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis. Cell Reports, 42(7), Article 112801. https://doi.org/10.1016/j.celrep.2023.112801

Huang, H, Jing, B, Zhu, F, Jiang, W, Tang, P, Shi, L, Chen, H, Ren, G, Xia, S, Wang, L, Cui, Y, Yang, Z, Platero, AJ, Hutchins, AP, Chen, M, Worley, PF & Xiao, B 2023, 'Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis', Cell Reports, vol. 42, no. 7, 112801. https://doi.org/10.1016/j.celrep.2023.112801

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title = "Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis",

abstract = "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.",

keywords = "CP: Developmental biology, CP: Neuroscience, DLK1, Raptor, Rheb, hypomyelination, mTORC1, myelination, myelination deficit, neuron-OPC interaction, neuron-glia interaction, oligodendrocyte differentiation",

author = "Haijiao Huang and Bo Jing and Feiyan Zhu and Wanxiang Jiang and Ping Tang and Liyang Shi and Huiting Chen and Guoru Ren and Shiyao Xia and Luoling Wang and Yiyuan Cui and Zhiwen Yang and Platero, {Alexander J.} and Hutchins, {Andrew P.} and Mina Chen and Worley, {Paul F.} and Bo Xiao",

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doi = "10.1016/j.celrep.2023.112801",

language = "English (US)",

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T1 - Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis

AU - Huang, Haijiao

AU - Jing, Bo

AU - Zhu, Feiyan

AU - Jiang, Wanxiang

AU - Tang, Ping

AU - Shi, Liyang

AU - Chen, Huiting

AU - Ren, Guoru

AU - Xia, Shiyao

AU - Wang, Luoling

AU - Cui, Yiyuan

AU - Yang, Zhiwen

AU - Platero, Alexander J.

AU - Hutchins, Andrew P.

AU - Chen, Mina

AU - Worley, Paul F.

AU - Xiao, Bo

PY - 2023/7/25

Y1 - 2023/7/25

N2 - 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.

AB - 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.

KW - CP: Developmental biology

KW - CP: Neuroscience

KW - DLK1

KW - Raptor

KW - Rheb

KW - hypomyelination

KW - mTORC1

KW - myelination

KW - myelination deficit

KW - neuron-OPC interaction

KW - neuron-glia interaction

KW - oligodendrocyte differentiation

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DO - 10.1016/j.celrep.2023.112801

M3 - Article

C2 - 37463107

AN - SCOPUS:85165395885

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 7

M1 - 112801

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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