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.
Andrews
Melissa R
MR
Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2PY, United Kingdom.
Czvitkovich
Stefan
S
Dassie
Elisa
E
Vogelaar
Christina F
CF
Faissner
Andreas
A
Blits
Bas
B
Gage
Fred H
FH
ffrench-Constant
Charles
C
Fawcett
James W
JW
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D039001:Integrin alpha Chains / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D018613:Microscopy, Confocal; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000502:physiology* / Q000648:ultrastructure; D055495:Neurogenesis / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D019063:Tenascin / Q000378:metabolism*
D039001:Integrin alpha Chains; D019063:Tenascin; C084613:integrin alpha9