title: Oligodendrocyte precursor cell-intrinsic effect of Rheb1 controls differentiation and mediates mTORC1-dependent myelination in brain.
abstract: Rheb1 is an immediate early gene that functions to activate mammalian target of rapamycin (mTor) selectively in complex 1 (mTORC1). We have demonstrated previously that Rheb1 is essential for myelination in the CNS using a Nestin-Cre driver line that deletes Rheb1 in all neural cell lineages, and recent studies using oligodendrocyte-specific CNP-Cre have suggested a preferential role for mTORC1 is myelination in the spinal cord. Here, we examine the role of Rheb1/mTORC1 in mouse oligodendrocyte lineage using separate Cre drivers for oligodendrocyte progenitor cells (OPCs) including Olig1-Cre and Olig2-Cre as well as differentiated and mature oligodendrocytes including CNP-Cre and Tmem10-Cre. Deletion of Rheb1 in OPCs impairs their differentiation to mature oligodendrocytes. This is accompanied by reduced OPC cell-cycle exit suggesting a requirement for Rheb1 in OPC differentiation. The effect of Rheb1 on OPC differentiation is mediated by mTor since Olig1-Cre deletion of mTor phenocopies Olig1-Cre Rheb1 deletion. Deletion of Rheb1 in mature oligodendrocytes, in contrast, does not disrupt developmental myelination or myelin maintenance. Loss of Rheb1 in OPCs or neural progenitors does not affect astrocyte formation in gray and white matter, as indicated by the pan-astrocyte marker Aldh1L1. We conclude that OPC-intrinsic mTORC1 activity mediated by Rheb1 is critical for differentiation of OPCs to mature oligodendrocytes, but that mature oligodendrocytes do not require Rheb1 to make myelin or maintain it in the adult brain. These studies reveal mechanisms that may be relevant for both developmental myelination and impaired remyelination in myelin disease.
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Wanxiang
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Li
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Junyan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Bu
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zou
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Shouyang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Weiwei
authors.identifier: http://orcid.org/0000-0002-6386-1858
authors.initials: W
authors.lastname: Yang
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Liping
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Pediatrics, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and.
authors.forename: Qing R
authors.initials: QR
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China.
authors.forename: Mina
authors.initials: M
authors.lastname: Chen
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, bxiao365@yahoo.com pworley@jhmi.edu.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.affiliation: Neuroscience and Metabolism Research, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, Department of Neurosurgery, West China Hospital, Sichuan University, 610041 Chengdu, P.R. China bxiao365@yahoo.com pworley@jhmi.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000254:growth & development*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D046912:Multiprotein Complexes / Q000235:genetics / Q000502:physiology*; D009186:Myelin Sheath / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology*; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; C494786:Olig1 protein, mouse; C490213:Rheb protein, mouse
keywords: OPC; Rheb1; differentiation; mTORC1; myelination