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Integrin Activation Promotes Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans by Enhancing Integrin Signaling
Open accessAbstract
Chondroitin sulfate proteoglycans (CSPGs) are upregulated after CNS lesions, where they inhibit axon regeneration. In order for axon growth and regeneration to occur, surface integrin receptors must interact with surrounding extracellular matrix molecules. We have explored the hypothesis that CSPGs inhibit regeneration by inactivating integrins and that forcing integrins into an active state might overcome this inhibition. Using cultured rat sensory neurons, we show that the CSPG aggrecan inhibits laminin-mediated axon growth by impairing integrin signaling via decreasing phosphorylated FAK (pFAK) and pSrc levels, without affecting surface integrin levels. Forcing integrin activation and signaling by manganese or an activating antibody TS2/16 reversed the inhibitory effect of aggrecan on mixed aggrecan/laminin surfaces, and enhanced axon growth from cultured rat sensory neurons (manganese) and human embryonic stem cell-derived motoneurons (TS2/16). The inhibitory effect of Nogo-A can also be reversed by integrin activation. These results suggest that inhibition by CSPGs can act via inactivation of integrins, and that activation of integrins is a potential method for improving axon regeneration after injury.
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“Previous studies revealed an interaction between β1-integrins and CSPGs (Tan et al., 2011;Wu et al., 2002).”
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 Tan et al., 2011
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“A potential mechanism of CSPG-mediated repulsion may be through control of integrins.”
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 Tan et al., 2011
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“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 Tan et al., 2011
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Metadata
- Authors
- Tan, C. L., Kwok, J. C. F., Patani, R., ffrench-Constant, C., Chandran, S., & Fawcett, J. W.
- Affiliations
- University of Cambridge (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-04-27
- Volume
- 31
- Issue
- 17
- Pages
- 6289-6295
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3116378
- OpenAlex
- W2068815747
- Cited by
- 160
- References
- 38
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 1 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 16 · 2017: 7 · 2016: 8 · 2015: 13 · 2014: 19 · 2013: 12 · 2012: 19
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust
- British Heart Foundation (SP/10/003/28287)
- Motor Neurone Disease Association
- European Commission
- Henry Smith Charity
- John and Lucille Van Geest Foundation
- Medical Research Council
- 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
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- integrin activation, chondroitin sulfate proteoglycans, axon regeneration, aggrecan, laminin, focal adhesion kinase, Src kinase, Nogo-A, sensory neurons, motor neurons, extracellular matrix, central nervous system injury, integrin signaling
- MeSH terms
- Animals, Antibodies, Axons, Cells, Cultured, Dose-Response Relationship, Drug, Drug Interactions, Ganglia, Spinal, Gene Expression Regulation, Humans, Male, Manganese, Neural Inhibition, Neurons, Chondroitin Sulfate Proteoglycans, Time Factors, Signal Transduction, Integrins, Rats, Sprague-Dawley, Chondroitin ABC Lyase, Lamins, Rats, Aggrecans
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