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Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration

Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration
Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration

Damaged CNS axons are prevented from regenerating by an environment containing many inhibitory factors. They also lack an integrin that interacts with tenascin-C, the main extracellular matrix glycoprotein of the CNS, which is upregulated after injury. The alpha9beta1 integrin heterodimer is a receptor for the nonalternatively spliced region of tenascin-C, but the alpha9 subunit is absent in adult neurons. In this study, we show that PC12 cells and adult rat dorsal root ganglion (DRG) neurons do not extend neurites on tenascin-C. However, after forced expression of alpha9 integrin, extensive neurite outgrowth from PC12 cells and adult rat DRG neurons occurs. Moreover, both DRG neurons and PC12 cells secrete tenascin-C, enabling alpha9-transfected cells to grow axons on tissue culture plastic. Using adeno-associated viruses to express alpha9 integrin in vivo in DRGs, we examined axonal regeneration after cervical dorsal rhizotomy or dorsal column crush in the adult rat. After rhizotomy, significantly more dorsal root axons regrew into the dorsal root entry zone at 6 weeks after injury in alpha9 integrin-expressing animals than in green fluorescent protein (GFP) controls. Similarly, after a dorsal column crush injury, there was significantly more axonal growth into the lesion site compared with GFP controls at 6 weeks after injury. Behavioral analysis after spinal cord injury revealed that both experimental and control groups had an increased withdrawal latency in response to mechanical stimulation when compared with sham controls; however, in response to heat stimulation, normal withdrawal latencies returned after alpha9 integrin treatment but remained elevated in control groups.

0270-6474
5546-5557
Andrews, Melissa R
ae987a2f-878e-4ae3-a7a3-a7170712096c
Czvitkovich, Stefan
c6f7c202-1117-491f-aca6-3184321f112d
Dassie, Elisa
18566ce2-048b-47b8-928b-1c2baccf149a
Vogelaar, Christina F
01c6b2cd-5c25-4143-ac28-9174336f51a6
Faissner, Andreas
c19f1d2b-1cbb-43ba-a45d-7d9c9c2cb10e
Blits, Bas
424cb0bc-63d2-4112-a2d5-c5ddd014790c
Gage, Fred H
5f67b7de-f722-4ab3-942b-93a3ce44a2ca
ffrench-Constant, Charles
e9a015d3-a5b8-4789-bd19-d21d7dcabf77
Fawcett, James W
4549730e-9f62-45b8-820b-8a9c98d1058b
Andrews, Melissa R
ae987a2f-878e-4ae3-a7a3-a7170712096c
Czvitkovich, Stefan
c6f7c202-1117-491f-aca6-3184321f112d
Dassie, Elisa
18566ce2-048b-47b8-928b-1c2baccf149a
Vogelaar, Christina F
01c6b2cd-5c25-4143-ac28-9174336f51a6
Faissner, Andreas
c19f1d2b-1cbb-43ba-a45d-7d9c9c2cb10e
Blits, Bas
424cb0bc-63d2-4112-a2d5-c5ddd014790c
Gage, Fred H
5f67b7de-f722-4ab3-942b-93a3ce44a2ca
ffrench-Constant, Charles
e9a015d3-a5b8-4789-bd19-d21d7dcabf77
Fawcett, James W
4549730e-9f62-45b8-820b-8a9c98d1058b

Andrews, Melissa R, Czvitkovich, Stefan, Dassie, Elisa, Vogelaar, Christina F, Faissner, Andreas, Blits, Bas, Gage, Fred H, ffrench-Constant, Charles and Fawcett, James W (2009) Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. Journal of Neuroscience, 29 (17), 5546-5557. (doi:10.1523/JNEUROSCI.0759-09.2009).

Record type: Article

Abstract

Damaged CNS axons are prevented from regenerating by an environment containing many inhibitory factors. They also lack an integrin that interacts with tenascin-C, the main extracellular matrix glycoprotein of the CNS, which is upregulated after injury. The alpha9beta1 integrin heterodimer is a receptor for the nonalternatively spliced region of tenascin-C, but the alpha9 subunit is absent in adult neurons. In this study, we show that PC12 cells and adult rat dorsal root ganglion (DRG) neurons do not extend neurites on tenascin-C. However, after forced expression of alpha9 integrin, extensive neurite outgrowth from PC12 cells and adult rat DRG neurons occurs. Moreover, both DRG neurons and PC12 cells secrete tenascin-C, enabling alpha9-transfected cells to grow axons on tissue culture plastic. Using adeno-associated viruses to express alpha9 integrin in vivo in DRGs, we examined axonal regeneration after cervical dorsal rhizotomy or dorsal column crush in the adult rat. After rhizotomy, significantly more dorsal root axons regrew into the dorsal root entry zone at 6 weeks after injury in alpha9 integrin-expressing animals than in green fluorescent protein (GFP) controls. Similarly, after a dorsal column crush injury, there was significantly more axonal growth into the lesion site compared with GFP controls at 6 weeks after injury. Behavioral analysis after spinal cord injury revealed that both experimental and control groups had an increased withdrawal latency in response to mechanical stimulation when compared with sham controls; however, in response to heat stimulation, normal withdrawal latencies returned after alpha9 integrin treatment but remained elevated in control groups.

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More information

Accepted/In Press date: 9 March 2009
Published date: 29 April 2009
Organisations: Biomedicine

Identifiers

Local EPrints ID: 404993
URI: https://eprints.soton.ac.uk/id/eprint/404993
ISSN: 0270-6474
PURE UUID: 174d7d16-90c3-4fc8-b67a-783a4b5761da
ORCID for Melissa R Andrews: ORCID iD orcid.org/0000-0001-5960-5619

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Date deposited: 26 Jan 2017 16:41
Last modified: 20 Jul 2019 00:28

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Contributors

Author: Stefan Czvitkovich
Author: Elisa Dassie
Author: Christina F Vogelaar
Author: Andreas Faissner
Author: Bas Blits
Author: Fred H Gage
Author: Charles ffrench-Constant
Author: James W Fawcett

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