title: Integrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling.
abstract: 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.
authors.affiliation: Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
authors.forename: Chin Lik
authors.initials: CL
authors.lastname: Tan
authors.forename: Jessica C F
authors.initials: JC
authors.lastname: Kwok
authors.forename: Rickie
authors.initials: R
authors.lastname: Patani
authors.forename: Charles
authors.initials: C
authors.lastname: Ffrench-Constant
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
authors.forename: James W
authors.initials: JW
authors.lastname: Fawcett
mesh_terms: D053674:Aggrecans / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D034882:Lamins / Q000494:pharmacology; D008297:Male; D008345:Manganese / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D053674:Aggrecans; D000906:Antibodies; D011508:Chondroitin Sulfate Proteoglycans; D016023:Integrins; D034882:Lamins; D008345:Manganese; D019765:Chondroitin ABC Lyase