title: Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors.
abstract: Chondroitin sulfate proteoglycans (CSPGs) are a family of extracellular matrix molecules with various functions in regulating tissue morphogenesis, cell division, and axon guidance. A number of CSPGs are highly upregulated by reactive glial scar tissues after injuries and form a strong barrier for axonal regeneration in the adult vertebrate CNS. Although CSPGs may negatively regulate axonal growth via binding and altering activity of other growth-regulating factors, the molecular mechanisms by which CSPGs restrict axonal elongation are not well understood. Here, we identified a novel receptor mechanism whereby CSPGs inhibit axonal growth via interactions with neuronal transmembrane leukocyte common antigen-related phosphatase (LAR). CSPGs bind LAR with high affinity in transfected COS-7 cells and coimmunoprecipitate with LAR expressed in various tissues including the brain and spinal cord. CSPG stimulation enhances activity of LAR phosphatase in vitro. Deletion of LAR in knock-out mice or blockade of LAR with sequence-selective peptides significantly overcomes neurite growth restrictions of CSPGs in neuronal cultures. Intracellularly, CSPG-LAR interaction mediates axonal growth inhibition of neurons partially via inactivating Akt and activating RhoA signals. Systemic treatments with LAR-targeting peptides in mice with thoracic spinal cord transection injuries induce significant axon growth of descending serotonergic fibers in the vicinity of the lesion and beyond in the caudal spinal cord and promote locomotor functional recovery. Identification of LAR as a novel CSPG functional receptor provides a therapeutic basis for enhancing axonal regeneration and functional recovery after CNS injuries in adult mammals.
authors: Department of Neurology and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA.
authors: Daniel
authors: D
authors: Fisher
authors: Bin
authors: B
authors: Xing
authors: John
authors: J
authors: Dill
authors: Hui
authors: H
authors: Li
authors: Hai Hiep
authors: HH
authors: Hoang
authors: Zhenze
authors: Z
authors: Zhao
authors: Xiao-Li
authors: XL
authors: Yang
authors: Robert
authors: R
authors: Bachoo
authors: Stephen
authors: S
authors: Cannon
authors: Frank M
authors: FM
authors: Longo
authors: Morgan
authors: M
authors: Sheng
authors: Jerry
authors: J
authors: Silver
authors: Shuxin
authors: S
authors: Li
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011485:Protein Binding / Q000502:physiology; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000502:physiology*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D006131:Growth Inhibitors; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2