Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors

Daniel Fisher, Bin Xing, John Dill, Hui Li, Hai Hiep Hoang, Zhenze Zhao, Xiao Li Yang, Robert Bachoo, Stephen Cannon, Frank M. Longo, Morgan Sheng, Jerry Silver, Shuxin Li

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

Abstract

Chondroitin sulfate proteoglycans (CSPGs) are a family of extra cellular 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 forma 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 axonalelongationare not well understood. Here, we identified a novel receptor mechanism where byCSPGs inhibitaxonal growth via interactions with neuronal transmembrane leukocyte common antigen-related phosphatase(LAR).CSPGs bind LAR with high affinity in transfected COS-7cellsand coimmuno precipitate 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.

Original languageEnglish (US)
Pages (from-to)14051-14066
Number of pages16
JournalJournal of Neuroscience
Volume31
Issue number40
DOIs
StatePublished - Oct 5 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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