Full length talin stimulates integrin activation and axon regeneration.
Molecular and Cellular Neuroscience
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Tan, C. L., Kwok, J., Heller, J. P., Zhao, R., Eva, R., & Fawcett, J. (2015). Full length talin stimulates integrin activation and axon regeneration.. Molecular and Cellular Neuroscience, 68 1-8. https://doi.org/10.1016/j.mcn.2015.03.011
Integrin function is regulated by activation involving conformational changes that modulate ligand-binding affinity and downstream signaling. Activation is regulated through inside-out signaling which is controlled by many signaling pathways via a final common pathway through kindlin and talin, which bind to the intracellular tail of beta integrins. Previous studies have shown that the axon growth inhibitory molecules NogoA and chondroitin sulfate proteoglycans (CSPGs) inactivate integrins. Overexpressing kindlin-1 in dorsal root ganglion (DRG) neurons activates integrins, enabling their axons to overcome inhibitory molecules in the environment, and promoting regeneration in vivo following dorsal root crush. Other studies have indicated that expression of the talin head alone or with kindlin can enhance integrin activation. Here, using adult rat DRG neurons, we investigate the effects of overexpressing various forms of talin on axon growth and integrin signaling. We found that overexpression of the talin head activated axonal integrins but inhibited downstream signaling via FAK, and did not promote axon growth. Similarly, co-expression of the talin head and kindlin-1 prevented the growth-promoting effect of kindlin-1, suggesting that the talin head acts as a form of dominant negative for integrin function. Using full-length talin constructs in PC12 cells we observed that neurite growth was enhanced by the expression of wild-type talin and more so by two ‘activated’ forms of talin produced by point mutation (on laminin and aggrecan–laminin substrates). Nevertheless, co-expression of full-length talin with kindlin did not promote neurite growth more than either molecule alone. In vivo, we find that talin is present in PNS axons (sciatic nerve), and also in CNS axons of the corticospinal tract.
Integrins, Axon growth, Axon regeneration, Talin, Kindlin, Cytoskeleton, Cell adhesion
This work was funded by grants from the Medical Research Council (G1000864), the Henry Smith Charity, the Christopher and Dana Reeve Foundation, the John and Lucille van Geest Foundation, the European Union Framework 7 Programmes Spinal Cord Repair (201144) and Plasticise (223524), and the NIHR Cambridge Biomedical Research Centre. CLT was supported by the Merck, Sharpe and Dohme Fund. We thank Rienhardt Fassler for kindlin constructs and advice, David Critchley for talin antibodies and constructs and Mark Ginsberg for talin constructs.
MEDICAL RESEARCH COUNCIL (G1000864)
European Commission (223524)
EC FP7 CP (201144)
External DOI: https://doi.org/10.1016/j.mcn.2015.03.011
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247853
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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