title: The polarity protein Scribble regulates myelination and remyelination in the central nervous system.
abstract: The development and regeneration of myelin by oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), requires profound changes in cell shape that lead to myelin sheath initiation and formation. Here, we demonstrate a requirement for the basal polarity complex protein Scribble in CNS myelination and remyelination. Scribble is expressed throughout oligodendroglial development and is up-regulated in mature oligodendrocytes where it is localised to both developing and mature CNS myelin sheaths. Knockdown of Scribble expression in cultured oligodendroglia results in disrupted morphology and myelination initiation. When Scribble expression is conditionally eliminated in the myelinating glia of transgenic mice, myelin initiation in CNS is disrupted, both during development and following focal demyelination, and longitudinal extension of the myelin sheath is disrupted. At later stages of myelination, Scribble acts to negatively regulate myelin thickness whilst suppressing the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAP) kinase pathway, and localises to non-compact myelin flanking the node of Ranvier where it is required for paranodal axo-glial adhesion. These findings demonstrate an essential role for the evolutionarily-conserved regulators of intracellular polarity in myelination and remyelination.
authors: MRC Centre for Regenerative Medicine and MS Society/University of Edinburgh Centre for Translational Research, Scottish Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
authors: Andrew A
authors: AA
authors: Jarjour
authors: MRC Centre for Regenerative Medicine and MS Society/University of Edinburgh Centre for Translational Research, Scottish Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
authors: Amanda
authors: A
authors: Boyd
authors: Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia.
authors: Lukas E
authors: LE
authors: Dow
authors: MRC Centre for Regenerative Medicine and MS Society/University of Edinburgh Centre for Translational Research, Scottish Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
authors: Rebecca K
authors: RK
authors: Holloway
authors: Max Planck Institute for Experimental Medicine, Göttingen, Germany.
authors: Sandra
authors: S
authors: Goebbels
authors: Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors: Patrick O
authors: PO
authors: Humbert
authors: MRC Centre for Regenerative Medicine and MS Society/University of Edinburgh Centre for Translational Research, Scottish Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
authors: Anna
authors: A
authors: Williams
authors: MRC Centre for Regenerative Medicine and MS Society/University of Edinburgh Centre for Translational Research, Scottish Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
authors: Charles
authors: C
authors: ffrench-Constant
mesh_terms: D000818:Animals; D016764:Cell Polarity; D002490:Central Nervous System / Q000378:metabolism* / Q000648:ultrastructure; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000378:metabolism* / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C508433:scrib protein, mouse