Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors
Name
Fisher-2011-Leukocyte Common Ant.pdf
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5.4 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Sheng, Morgan Hwa-Tze
Fisher, Daniel
Xing, Bin
Dill, John
Li, Hui
Hoang, Hai Hiep
Zhao, Zhenze
Yang, Xiao-Li
Bachoo, Robert
Cannon, Stephen
Date Issued
October 2011
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Citation
Fisher, D. et al. “Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors.” Journal of Neuroscience 31.40 (2011): 14051–14066.
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
RIKEN-MIT Center for Neural Circuit Genetics
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DOI of Published Version
https://doi.org/10.1523/jneurosci.1737-11.2011
