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Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration

Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration
Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration

Growing and regenerating axons need to interact with the molecules in the extracellular matrix as they traverse through their environment. An important group of receptors that serve this function is the integrin superfamily of cell surface receptors, which are evolutionarily conserved αβ heterodimeric transmembrane proteins. The function of integrins is controlled by regulating the affinity for ligands (also called "integrin activation"). Previous results have shown that CNS inhibitory molecules inactivate axonal integrins, while enhancing integrin activation can promote axon growth from neurons cultured on inhibitory substrates. We tested two related molecules, kindlin-1 and kindlin-2 (Fermitin family members 1 and 2), that can activate β1, β2, and β3 integrins, for their effects on integrin signaling and integrin-mediated axon growth in rat sensory neurons. We determined that kindlin-2, but not kindlin-1, is endogenously expressed in the nervous system. Knocking down kindlin-2 levels in cultured sensory neurons impaired their ability to extend axons, but this was partially rescued by kindlin-1 expression. Overexpression of kindlin-1, but not kindlin-2, in cultured neurons increased axon growth on an inhibitory aggrecan substrate. This was found to be associated with enhanced integrin activation and signaling within the axons. Additionally, in an in vivo rat dorsal root injury model, transduction of dorsal root ganglion neurons to express kindlin-1 promoted axon regeneration across the dorsal root entry zone and into the spinal cord. These animals demonstrated improved recovery of thermal sensation following injury. Our results therefore suggest that kindlin-1 is a potential tool for improving axon regeneration after nervous system lesions.

0270-6474
7325-35
Tan, Chin Lik
ed3a370d-3e74-4746-a711-0c47a1094bbf
Andrews, Melissa R.
ae987a2f-878e-4ae3-a7a3-a7170712096c
Kwok, Jessica C.F.
009d0931-72ad-4978-963e-e9dce272644a
Heintz, Tristan G.P.
779653e6-9075-484d-b999-bf0bd8e82783
Gumy, Laura F.
1a6e79ab-133f-49e2-a4a3-f132e74c5c6e
Fässler, Reinhard
fe0d5abd-bccc-45fc-86b0-2cda453a6800
Fawcett, James W.
4549730e-9f62-45b8-820b-8a9c98d1058b
Tan, Chin Lik
ed3a370d-3e74-4746-a711-0c47a1094bbf
Andrews, Melissa R.
ae987a2f-878e-4ae3-a7a3-a7170712096c
Kwok, Jessica C.F.
009d0931-72ad-4978-963e-e9dce272644a
Heintz, Tristan G.P.
779653e6-9075-484d-b999-bf0bd8e82783
Gumy, Laura F.
1a6e79ab-133f-49e2-a4a3-f132e74c5c6e
Fässler, Reinhard
fe0d5abd-bccc-45fc-86b0-2cda453a6800
Fawcett, James W.
4549730e-9f62-45b8-820b-8a9c98d1058b

Tan, Chin Lik, Andrews, Melissa R., Kwok, Jessica C.F., Heintz, Tristan G.P., Gumy, Laura F., Fässler, Reinhard and Fawcett, James W. (2012) Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration. Journal of Neuroscience, 32 (21), 7325-35. (doi:10.1523/JNEUROSCI.5472-11.2012).

Record type: Article

Abstract

Growing and regenerating axons need to interact with the molecules in the extracellular matrix as they traverse through their environment. An important group of receptors that serve this function is the integrin superfamily of cell surface receptors, which are evolutionarily conserved αβ heterodimeric transmembrane proteins. The function of integrins is controlled by regulating the affinity for ligands (also called "integrin activation"). Previous results have shown that CNS inhibitory molecules inactivate axonal integrins, while enhancing integrin activation can promote axon growth from neurons cultured on inhibitory substrates. We tested two related molecules, kindlin-1 and kindlin-2 (Fermitin family members 1 and 2), that can activate β1, β2, and β3 integrins, for their effects on integrin signaling and integrin-mediated axon growth in rat sensory neurons. We determined that kindlin-2, but not kindlin-1, is endogenously expressed in the nervous system. Knocking down kindlin-2 levels in cultured sensory neurons impaired their ability to extend axons, but this was partially rescued by kindlin-1 expression. Overexpression of kindlin-1, but not kindlin-2, in cultured neurons increased axon growth on an inhibitory aggrecan substrate. This was found to be associated with enhanced integrin activation and signaling within the axons. Additionally, in an in vivo rat dorsal root injury model, transduction of dorsal root ganglion neurons to express kindlin-1 promoted axon regeneration across the dorsal root entry zone and into the spinal cord. These animals demonstrated improved recovery of thermal sensation following injury. Our results therefore suggest that kindlin-1 is a potential tool for improving axon regeneration after nervous system lesions.

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More information

Accepted/In Press date: 27 March 2012
Published date: 23 May 2012
Organisations: Biomedicine

Identifiers

Local EPrints ID: 411364
URI: http://eprints.soton.ac.uk/id/eprint/411364
ISSN: 0270-6474
PURE UUID: 4ac673e4-463e-4a65-91d4-4435777c78f8
ORCID for Melissa R. Andrews: ORCID iD orcid.org/0000-0001-5960-5619

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Date deposited: 19 Jun 2017 16:31
Last modified: 03 Dec 2019 01:28

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Contributors

Author: Chin Lik Tan
Author: Jessica C.F. Kwok
Author: Tristan G.P. Heintz
Author: Laura F. Gumy
Author: Reinhard Fässler
Author: James W. Fawcett

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