title: Death receptor 6 negatively regulates oligodendrocyte survival, maturation and myelination.
abstract: Survival and differentiation of oligodendrocytes are important for the myelination of central nervous system (CNS) axons during development and crucial for myelin repair in CNS demyelinating diseases such as multiple sclerosis. Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. DR6 is expressed strongly in immature oligodendrocytes and weakly in mature myelin basic protein (MBP)-positive oligodendrocytes. Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. Treatment with a DR6 antagonist antibody promotes remyelination in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE) models. Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. These studies reveal a pivotal role for DR6 signaling in immature oligodendrocyte maturation and myelination that may provide new therapeutic avenues for the treatment of demyelination disorders such as multiple sclerosis.
authors: Biogen Idec, Cambridge, Massachusetts, USA. sha.mi@biogenidec.com
authors: Sha
authors: S
authors: Mi
authors: Xinhua
authors: X
authors: Lee
authors: Yinghui
authors: Y
authors: Hu
authors: Benxiu
authors: B
authors: Ji
authors: Zhaohui
authors: Z
authors: Shao
authors: Weixing
authors: W
authors: Yang
authors: Guanrong
authors: G
authors: Huang
authors: Lee
authors: L
authors: Walus
authors: Kenneth
authors: K
authors: Rhodes
authors: Bang Jian
authors: BJ
authors: Gong
authors: Robert H
authors: RH
authors: Miller
authors: R Blake
authors: RB
authors: Pepinsky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism / Q000628:therapy; D009186:Myelin Sheath / Q000378:metabolism* / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; D053148:Caspase 3