title: Phosphorylation of LKB1/Par-4 establishes Schwann cell polarity to initiate and control myelin extent.
abstract: The Schwann cell (SC)-axon interface represents a membrane specialization that integrates axonal signals to coordinate cytoskeletal dynamics resulting in myelination. Here we show that LKB1/Par-4 is asymmetrically localized to the SC-axon interface and co-localizes with the polarity protein Par-3. Using purified SCs and myelinating cocultures, we demonstrate that localization is dependent on the phosphorylation of LKB1 at serine-431. SC-specific deletion of LKB1 significantly attenuates developmental myelination, delaying the initiation and altering the myelin extent into adulthood, resulting in a 30% reduction in the conduction velocity along the adult sciatic nerves. Phosphorylation of LKB1 by protein kinase A is essential to establish the asymmetric localization of LKB1 and Par-3 and rescues the delay in myelination observed in the SC-specific knockout of LKB1. Our findings suggest that SC polarity may coordinate multiple signalling complexes that couple SC-axon contact to the redistribution of specific membrane components necessary to initiate and control myelin extent.
authors.affiliation: Department of Neurology and Program in Neurosciences, University of California, San Francisco, California 94158, USA.
authors.forename: Yun-An A
authors.initials: YA
authors.lastname: Shen
authors.affiliation: 1] Department of Pediatrics, Brain Cancer Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 [2] Department of Pediatrics and Obstetrics/Gynecology, State Key Laboratory of Biotherapy, Cancer Center, West China Second Hospital, Sichuan University, Chengdu 61004, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology and Physiology and Programs in Neurosciences, University of California, San Francisco, California 94143, USA.
authors.forename: Dang Q
authors.initials: DQ
authors.lastname: Dao
authors.affiliation: Department of Neurology and Program in Neurosciences, University of California, San Francisco, California 94158, USA.
authors.forename: Sonia R
authors.initials: SR
authors.lastname: Mayoral
authors.affiliation: Department of Pediatrics, Brain Cancer Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Laiman
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Cellular Neurobiology, Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.affiliation: Department of Ophthalmology and Physiology and Programs in Neurosciences, University of California, San Francisco, California 94143, USA.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Ullian
authors.affiliation: Department of Neurology and Program in Neurosciences, University of California, San Francisco, California 94158, USA.
authors.forename: Jonah R
authors.initials: JR
authors.lastname: Chan
authors.affiliation: Department of Pediatrics, Brain Cancer Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D016764:Cell Polarity; D002478:Cells, Cultured; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012583:Schwann Cells / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C115084:Pard3 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases