Skip Navigation


Brain Advance Access originally published online on April 13, 2006
Brain 2006 129(6):1517-1533; doi:10.1093/brain/awl080
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
129/6/1517    most recent
awl080v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (7)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ahmed, Z.
Right arrow Articles by Logan, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ahmed, Z.
Right arrow Articles by Logan, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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, Ellen L. Suggate, Elspeth R. Brown, Russell G. Dent, Stephanie J. Armstrong, Lee B. Barrett, Martin Berry and Ann Logan

Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham Birmingham, UK

Correspondence to: Prof Ann Logan, Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK E-mail: a.logan{at}bham.ac.uk

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-{alpha} 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.

Key Words: regulated intramembranous proteolysis; optic nerve regeneration; RGC axon growth disinhibition; metalloproteases

Abbreviations: BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; CSPG, chondroitin sulphate proteoglycans; EGFR, epidermal growth factor receptor; MAG, myelin-associated glycoprotein; MMP, matrix metalloproteinases; NRM, non-regenerating model; NTF, neurotrophic factor; NgR, Nogo receptor; PN, peripheral nerve; RGC, retinal ganglion cell; Rho-GDI, Rho-GDP dissociation inhibitor; RIP, regulated intramembranous proteolysis; RM, regenerating model; TACE, tumour necrosis-{alpha} converting enzyme; TIMP, tissue inhibitors of MMP

Received December 22, 2005. Revised March 8, 2006. Accepted March 9, 2006.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
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]

Home page
 FASEB J.Home page
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]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.