Brain Advance Access published online on April 13, 2006
Brain, doi:10.1093/brain/awl080
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Birmingham, UK
* To whom correspondence should be addressed. When associated with the Nogo receptor (NgR), the transmembrane receptor p75NTR signals growth cone collapse. Arrest of CNS axon growth in vivo is mediated by CNS myelin-derived inhibitory ligands through either an unknown pathway after NgR- and Ca2+-dependent activation of the epidermal growth factor receptor (EGFR), and/or sequential Rho-A/ROCK/LIM-kinase/cofilin phosphorylation leading to actin depolymerization. Paradoxically, rat retinal ganglion cell (RGC) axons regenerate through the CNS myelin-rich transected optic nerve after intravitreal sciatic nerve grafting without inhibitory ligand neutralization. Here, we show that optic nerve regeneration in vivo correlates with Schwann cell-derived factor-induced cleavage of NgR and Nogo-A, and inactivation of p75NTR signalling by the induction of regulated intramembranous proteolysis (RIP) and the release of both extracellular (p75ECD) and intracellular (p75ICD) domains. Hence, Schwann cell-derived factors compromise inhibitory signalling by (i) antagonizing ligand/NgR binding with metalloproteinase-cleaved Nogo-A peptides; (ii) RIP of p75NTR; (iii) competitively blocking NgR/p75NTR clustering with soluble p75ECD; and (iv) consequent reduced downstream EGFR phosphorylation and suppression of Rho-A activation. Moreover, in RGC cultures, exogenous tumour necrosis-
Received December 22, 2005
Revised March 8, 2006
Accepted March 9, 2006
Article
Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro
Zubair Ahmed 1,
Ellen L. Suggate 1,
Elspeth R. Brown 1,
Russell G. Dent 1,
Stephanie J. Armstrong 1,
Lee B. Barrett 1,
Martin Berry 1,
and
Ann Logan 1 *
Ann Logan, E-mail: a.logan{at}bham.ac.uk
Abstract 
converting enzyme (TACE) initiates RIP of p75NTR, reduces EGFR phosphorylation, suppresses activation of Rho-A, cleaves the ECD from both NgR and TROY, and disinhibits neurotrophic factor (NTF) stimulated RGC neurite outgrowth in the presence of CNS myelin. Soluble NgRECD binds all CNS myelin-derived ligands and thus has the potential to act as an inhibitory signalling antagonist, but the role of TROY and its shed ectodomain in growth cone mobility is unknown. siRNA knockdown of p75NTR also inactivates Rho-A and disinhibits NTF-stimulated RGC neurite outgrowth in cultures with added CNS myelin. In all the above experimental paradigms, Schwann cell-derived factor/NTF-induced attenuation of NgR/p75NTR signalling suppresses EGFR activation, thereby potentiating axon growth disinhibition.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Charalambous, L. A. Hurst, and S. Thanos Engrafted Chicken Neural Tube-Derived Stem Cells Support the Innate Propensity for Axonal Regeneration within the Rat Optic Nerve Invest. Ophthalmol. Vis. Sci., August 1, 2008; 49(8): 3513 - 3524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. de Melo, Q.-P. Zhou, Q. Zhang, S. Zhang, M. Fonseca, J. T. Wigle, and D. D. Eisenstat Dlx2 homeobox gene transcriptional regulation of Trkb neurotrophin receptor expression during mouse retinal development Nucleic Acids Res., February 11, 2008; 36(3): 872 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Ahmed, G. Mazibrada, R. J. Seabright, R. G. Dent, M. Berry, and A. Logan TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin FASEB J, September 1, 2006; 20(11): 1939 - 1941. [Abstract] [Full Text] [PDF]
|
|