title: Low-density Lipoprotein Receptor-related Proteins in a Novel Mechanism of Axon Guidance and Peripheral Nerve Regeneration.
abstract: The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1 and LRP2) are emerging as important cell signaling mediators in modulating neuronal growth and repair. We examined whether LRP1 and LRP2 are able to mediate a specific aspect of neuronal growth: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemoattraction, which might have therapeutic potential. Using embryonic sensory neurons (rat dorsal root ganglia) in a growth cone turning assay, we tested a range of LRP1 and LRP2 ligands for the ability to guide growth cone navigation. Three ligands were chemorepulsive: α-2-macroglobulin, tissue plasminogen activator, and metallothionein III. Conversely, only one LRP ligand, metallothionein II, was found to be chemoattractive. Chemoattraction toward a gradient of metallothionein II was calcium-dependent, required the expression of both LRP1 and LRP2, and likely involves further co-receptors such as the tropomyosin-related kinase A (TrkA) receptor. The potential for LRP-mediated chemoattraction to mediate axonal regeneration was examined in vivo in a model of chemical denervation in adult rats. In these in vivo studies, metallothionein II was shown to enhance epidermal nerve fiber regeneration so that it was complete within 7 days compared with 14 days in saline-treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II-mediated chemotactic signal transduction and that they may form part of a signaling complex. Furthermore, the data suggest that LRP-mediated chemoattraction represents a novel, non-classical signaling system that has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system.
authors.affiliation: From the School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7001, Australia.
authors.forename: Lila M
authors.initials: LM
authors.lastname: Landowski
authors.affiliation: From the School of Medicine and.
authors.forename: Macarena
authors.initials: M
authors.lastname: Pavez
authors.affiliation: From the School of Medicine and.
authors.forename: Lachlan S
authors.initials: LS
authors.lastname: Brown
authors.affiliation: From the School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7001, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Gasperini
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7001, Australia.
authors.forename: Bruce V
authors.initials: BV
authors.lastname: Taylor
authors.affiliation: From the School of Medicine and.
authors.forename: Adrian K
authors.initials: AK
authors.lastname: West
authors.affiliation: From the School of Medicine and lisa.foa@utas.edu.au.
authors.forename: Lisa
authors.initials: L
authors.lastname: Foa
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects / Q000294:innervation; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000494:pharmacology / Q000627:therapeutic use; D009416:Nerve Regeneration / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D010525:Peripheral Nerves / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D034622:RNA Interference; D011817:Rabbits; D017207:Rats, Sprague-Dawley
chemical_list: D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D009419:Nerve Tissue Proteins; C021267:zinc thionein; D008668:Metallothionein
keywords: LRP1; LRP2; axon; cell signaling; growth cone; metallothionein; neurite outgrowth; neurobiology; regeneration