title: Schwann cell LRP1 regulates remak bundle ultrastructure and axonal interactions to prevent neuropathic pain.
abstract: Trophic support and myelination of axons by Schwann cells in the PNS are essential for normal nerve function. Herein, we show that deletion of the LDL receptor-related protein-1 (LRP1) gene in Schwann cells (scLRP1(-/-)) induces abnormalities in axon myelination and in ensheathment of axons by nonmyelinating Schwann cells in Remak bundles. These anatomical changes in the PNS were associated with mechanical allodynia, even in the absence of nerve injury. In response to crush injury, sciatic nerves in scLRP1(-/-) mice showed accelerated degeneration and Schwann cell death. Remyelinated axons were evident 20 d after crush injury in control mice, yet were largely absent in scLRP1(-/-) mice. In the partial nerve ligation model, scLRP1(-/-) mice demonstrated significantly increased and sustained mechanical allodynia and loss of motor function. Evidence for central sensitization in pain processing included increased p38MAPK activation and activation of microglia in the spinal cord. These studies identify LRP1 as an essential mediator of normal Schwann cell-axonal interactions and as a pivotal regulator of the Schwann cell response to PNS injury in vivo. Mice in which LRP1 is deficient in Schwann cells represent a model for studying how abnormalities in Schwann cell physiology may facilitate and sustain chronic pain.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Sumihisa
authors.initials: S
authors.lastname: Orita
authors.forename: Kenneth
authors.initials: K
authors.lastname: Henry
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mantuano
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Alice
authors.initials: A
authors.lastname: De Corato
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Ishikawa
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
authors.forename: Alban
authors.initials: A
authors.lastname: Gaultier
authors.forename: Melanie
authors.initials: M
authors.lastname: Pollack
authors.forename: Mark
authors.initials: M
authors.lastname: Ellisman
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
authors.forename: W Marie
authors.initials: WM
authors.lastname: Campana
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure*; D039481:CD11b Antigen / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006930:Hyperalgesia / Q000209:etiology / Q000235:genetics; D020287:In Situ Nick-End Labeling; D007211:Indoles; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009069:Movement Disorders / Q000209:etiology / Q000235:genetics; D004676:Myelin Basic Protein / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics; D010147:Pain Measurement; D010766:Phosphorylation / Q000235:genetics; D020671:Posterior Horn Cells / Q000473:pathology / Q000648:ultrastructure; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000473:pathology* / Q000648:ultrastructure; D012585:Sciatica / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D012678:Sensation Disorders / Q000209:etiology; D013116:Spinal Cord / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D039481:CD11b Antigen; D007211:Indoles; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D004676:Myelin Basic Protein; D011973:Receptors, LDL; D009418:S100 Proteins; D025521:Tumor Suppressor Proteins; C007293:DAPI; D048051:p38 Mitogen-Activated Protein Kinases
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