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Integrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling.

TitleIntegrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling.
Publication TypeJournal Article
Year of Publication2011
AuthorsTan CLik, Kwok JCF, Patani R, ffrench-Constant C, Chandran S, Fawcett JW
JournalJ Neurosci
Date Published2011 Apr 27
KeywordsAggrecans, Animals, Antibodies, Axons, Cells, Cultured, Chondroitin ABC Lyase, Chondroitin Sulfate Proteoglycans, Dose-Response Relationship, Drug, Drug Interactions, Ganglia, Spinal, Gene Expression Regulation, Humans, Integrins, Lamins, Male, Manganese, Neural Inhibition, Neurons, Rats, Rats, Sprague-Dawley, Signal Transduction, Time Factors

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.

Alternate JournalJ. Neurosci.
PubMed ID21525268
PubMed Central IDPMC3116378
Grant ListG0701518 / / Medical Research Council / United Kingdom
SP/10/003/28287 / / British Heart Foundation / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom