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Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors
Open accessAbstract
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.
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“LAR deletion in knock-out mice overcomes growth restriction of CSPGs on neurites in neuronal cultures, and treatments with LAR-targeting peptides or LAR knockout significantly improve axonal growth and behavioral recovery after spinal cord injury (Fisher et al., 2011;Xu et al., 2015).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Fisher et al., 2011
In the citing paper
“LAR deletion in knock-out mice overcomes growth restriction of CSPGs on neurites in neuronal cultures, and treatments with LAR-targeting peptides or LAR knockout significantly improve axonal growth and behavioral recovery after spinal cord injury (Fisher et al., 2011;Xu et al., 2015).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Fisher et al., 2011
In the citing paper
“LAR interacts with high levels of extracellular CSPGs, including versican, in both the normal and injured CNS.”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Fisher et al., 2011
In the citing paper
“Known CS/CSPG receptors are: contactin-1 (Mikami et al., 2009), receptor protein tyrosine phosphatase sigma (RPTPσ; Shen et al., 2009), leukocyte common antigen-related phosphatase (LAR; Fisher et al., 2011) and Nogo receptor (NgR) 1 and 3 (Dickendesher et al., 2012).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Fisher et al., 2011
In the citing paper
“Specifically, CSPGs, and particularly their GAG moieties, may act by i) binding to a specific receptor; ii) blocking the growth-promoting activity of integrins; iii) presenting growth-inhibitory proteins.”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Fisher et al., 2011
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Metadata
- Authors
- Fisher, D., Xing, B., Dill, J., Li, H., Hoang, H. H., Zhao, Z., Yang, X.-L., Bachoo, R., Cannon, S., Longo, F. M., Sheng, M., Silver, J., & Li, S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Case Western Reserve University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-10-05
- Volume
- 31
- Issue
- 40
- Pages
- 14051-14066
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3220601
- OpenAlex
- W2086085796
- Cited by
- 312
- References
- 77
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 7 · 2023: 13 · 2022: 23 · 2021: 22 · 2020: 15 · 2019: 19 · 2018: 28 · 2017: 24 · 2016: 14 · 2015: 36 · 2014: 39 · 2013: 32 · 2012: 17
- FWCI
- 11.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Christopher and Dana Reeve Foundation
- Morton Cure Paralysis Fund
- Paralyzed Veterans of America
- National Institutes of Health (NS025713)
- National Institute of Neurological Disorders and Stroke (R37NS025713, NS025713, R01NS025713, R21NS066114)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- chondroitin sulfate proteoglycans, axon growth inhibition, neurite outgrowth, glial scar, spinal cord transection, axon regeneration, Akt signaling, RhoA signaling, locomotor recovery, central nervous system injury
- MeSH terms
- Animals, Axons, Cells, Cultured, Chlorocebus aethiops, Female, Growth Inhibitors, Humans, Mice, Inbred C57BL, Mice, Mutant Strains, Protein Binding, Chondroitin Sulfate Proteoglycans, Mice, Knockout, COS Cells, Mice, Receptor-Like Protein Tyrosine Phosphatases, Class 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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