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The Journal of Neuroscience, April 29, 2009, 29(17):5546-5557; doi:10.1523/JNEUROSCI.0759-09.2009

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Development/Plasticity/Repair
9 Integrin Promotes Neurite Outgrowth on Tenascin-C and Enhances Sensory Axon Regeneration

Melissa R. Andrews,^1 * Stefan Czvitkovich,^1 * Elisa Dassie,¹ Christina F. Vogelaar,¹ Andreas Faissner,² Bas Blits,³ Fred H. Gage,⁴ Charles ffrench-Constant,¹ and James W. Fawcett¹

¹Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, United Kingdom, ²Department of Cell Morphology and Molecular Neurobiology, Faculty of Biology, Ruhr University Bochum, 44780 Bochum, Germany, ³Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands, and ⁴Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037

Correspondence should be addressed to Prof. James W. Fawcett, Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Robinson Way, Cambridge CB2 2PY, UK. Email: jf108{at}cam.ac.uk

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 9β1 integrin heterodimer is a receptor for the nonalternatively spliced region of tenascin-C, but the 9 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 9 integrin, extensive neurite outgrowth from PC12 cells and adult rat DRG neurons occurs. Moreover, both DRG neurons and PC12 cells secrete tenascin-C, enabling 9-transfected cells to grow axons on tissue culture plastic. Using adeno-associated viruses to express 9 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 9 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 9 integrin treatment but remained elevated in control groups.

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Received Feb. 13, 2009; accepted March 9, 2009.

Correspondence should be addressed to Prof. James W. Fawcett, Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Robinson Way, Cambridge CB2 2PY, UK. Email: jf108{at}cam.ac.uk

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