Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors
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 a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Society for Neuroscience
2012
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| Online Access: | http://hdl.handle.net/1721.1/73069 |
| _version_ | 1826191020144984064 |
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| author | Sheng, Morgan Hwa-Tze Fisher, Daniel Xing, Bin Dill, John Li, Hui Hoang, Hai Hiep Zhao, Zhenze Yang, Xiao-Li Bachoo, Robert Cannon, Stephen Longo, Frank M. Silver, Jerry Li, Shuxin |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Sheng, Morgan Hwa-Tze Fisher, Daniel Xing, Bin Dill, John Li, Hui Hoang, Hai Hiep Zhao, Zhenze Yang, Xiao-Li Bachoo, Robert Cannon, Stephen Longo, Frank M. Silver, Jerry Li, Shuxin |
| author_sort | Sheng, Morgan Hwa-Tze |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:49:10Z |
| format | Article |
| id | mit-1721.1/73069 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:49:10Z |
| publishDate | 2012 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/730692022-09-23T14:45:17Z Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors Sheng, Morgan Hwa-Tze Fisher, Daniel Xing, Bin Dill, John Li, Hui Hoang, Hai Hiep Zhao, Zhenze Yang, Xiao-Li Bachoo, Robert Cannon, Stephen Longo, Frank M. Silver, Jerry Li, Shuxin Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory RIKEN-MIT Center for Neural Circuit Genetics Sheng, Morgan Hwa-Tze 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. Paralyzed Veterans of America (Grant 2584) Paralyzed Veterans of America (Grant 2516) National Institutes of Health (U.S.) (Grant 1R21 NS066114-01A1) 2012-09-20T16:46:39Z 2012-09-20T16:46:39Z 2011-10 2011-08 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/73069 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. en_US http://dx.doi.org/10.1523/jneurosci.1737-11.2011 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience SFN |
| spellingShingle | Sheng, Morgan Hwa-Tze Fisher, Daniel Xing, Bin Dill, John Li, Hui Hoang, Hai Hiep Zhao, Zhenze Yang, Xiao-Li Bachoo, Robert Cannon, Stephen Longo, Frank M. Silver, Jerry Li, Shuxin Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors |
| title | Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors |
| title_full | Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors |
| title_fullStr | Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors |
| title_full_unstemmed | Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors |
| title_short | Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors |
| title_sort | leukocyte common antigen related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors |
| url | http://hdl.handle.net/1721.1/73069 |
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