机构：[1]Key Laboratory of Brain Functional Genomics of STCSM, Institute of Cognitive Neuroscience, East China Normal University, Shanghai 200062, China.[2]Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.[3]Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu 610041, China.[4]Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.[5]Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA.[6]Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07101, USA.[7]Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
Tuberous sclerosis complex-1 or 2 (TSC1/2) mutations cause white matter abnormalities, including myelin deficits in the CNS; however, underlying mechanisms are not fully understood. TSC1/2 negatively regulate the function of mTOR, which is required for oligodendrocyte differentiation. Here we report that, unexpectedly, constitutive activation of mTOR signalling by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death in mice, despite an initial increase of oligodendrocyte precursors during early development. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses by activating a PERK-eIF2α signalling axis and Fas-JNK apoptotic pathways. Enhancement of the phospho-eIF2α adaptation pathway by inhibition of Gadd34-PP1 phosphatase with guanabenz protects oligodendrocytes and partially rescues myelination defects in Tsc1 mutants. Thus, TSC1-mTOR signalling acts as an important checkpoint for maintaining oligodendrocyte homoeostasis, pointing to a previously uncharacterized ER stress mechanism that contributes to hypomyelination in tuberous sclerosis.
基金：
This study
was funded in part by grants from the US National Institutes of Health R01NS072427
and R01NS075243 to Q.R.L., NS082203 to T.L.W., the National Multiple Sclerosis Society
(RG 5332) to Q.R.L. and National Natural Science Foundation of China NSFC 31271134
to Hu.W.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2016]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Key Laboratory of Brain Functional Genomics of STCSM, Institute of Cognitive Neuroscience, East China Normal University, Shanghai 200062, China.[2]Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
共同第一作者：
通讯作者：
通讯机构：[2]Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.[7]Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
推荐引用方式(GB/T 7714)：
Jiang Minqing,Liu Lei,He Xuelian,et al.Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes.[J].Nature communications.2016,7:12185.doi:10.1038/ncomms12185.
APA：
Jiang Minqing,Liu Lei,He Xuelian,Wang Haibo,Lin Wensheng...&Lu Q Richard.(2016).Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes..Nature communications,7,
MLA：
Jiang Minqing,et al."Regulation of PERK-eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes.".Nature communications 7.(2016):12185
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