Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 102 (30): 10694-10699

Copyright © 2005 by the National Academy of Sciences.


Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

M. Douglas Benson, Mario I. Romero, Mark E. Lush, Q. Richard Lu, Mark Henkemeyer, and Luis F. Parada *

Center for Developmental Biology and Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9133

Communicated by Eric M. Shooter, Stanford University School of Medicine, Stanford, CA, June 3, 2005

Received for publication February 17, 2005.

Abstract: The inability of CNS axons to regenerate after traumatic spinal cord injury is due, in part, to the inhibitory effects of myelin. The three major previously identified constituents of this activity (Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein) were isolated based on their potent inhibition of axon outgrowth in vitro. All three myelin components transduce their inhibitory signals through the same Nogo receptor/p75 neurotrophin receptor/LINGO-1 (NgR1/p75/LINGO-1) complex. In this study, we considered that molecules known to act as repellants in vertebrate embryonic axonal pathfinding may also inhibit regeneration. In mice, ephrin-B3 functions during development as a midline repellant for axons of the corticospinal tract. We therefore investigated whether this repellant was expressed in the adult spinal cord and retained inhibitory activity. We demonstrate that ephrin-B3 is expressed in postnatal myelinating oligodendrocytes and, by using primary CNS neurons, show that ephrin-B3 accounts for an inhibitory activity equivalent to that of the other three myelin-based inhibitors, acting through p75, combined. Our data describe a known vertebrate axon guidance molecule as a myelin-based inhibitor of neurite outgrowth.

Key Words: spinal cord injury • regeneration • axon • Eph receptor

Freely available online through the PNAS open access option.

Abbreviations: CST, corticospinal tract; SCI, spinal cord injury; MAG, myelin associated glycoprotein; OMgp, oligodendrocyte myelin glycoprotein; NgR, Nogo receptor; CGN, cerebellar granule neuron; Nogo-66, 66-aa extracellular loop of Nogo; APC, adenomatous polyposis coli.

* To whom correspondence should be addressed. E-mail: luis.parada{at}

© 2005 by The National Academy of Sciences of the USA

Modifying expression of EphA4 and its downstream targets improves functional recovery after stroke.
R. Lemmens, T. Jaspers, W. Robberecht, and V. N. Thijs (2013)
Hum. Mol. Genet. 22, 2214-2220
   Abstract »    Full Text »    PDF »
Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury.
P. Duffy, X. Wang, C. S. Siegel, N. Tu, M. Henkemeyer, W. B. J. Cafferty, and S. M. Strittmatter (2012)
PNAS 109, 5063-5068
   Abstract »    Full Text »    PDF »
The Lipid Sulfatide Is a Novel Myelin-Associated Inhibitor of CNS Axon Outgrowth.
A. M. Winzeler, W. J. Mandemakers, M. Z. Sun, M. Stafford, C. T. Phillips, and B. A. Barres (2011)
J. Neurosci. 31, 6481-6492
   Abstract »    Full Text »    PDF »
Cortical Control of Adaptive Locomotion in Wild-Type Mice and Mutant Mice Lacking the Ephrin-Eph Effector Protein {alpha}2-Chimaerin.
C. O. Asante, A. Chu, M. Fisher, L. Benson, A. Beg, P. Scheiffele, and J. Martin (2010)
J Neurophysiol 104, 3189-3202
   Abstract »    Full Text »    PDF »
Genetic Deletion of Paired Immunoglobulin-Like Receptor B Does Not Promote Axonal Plasticity or Functional Recovery after Traumatic Brain Injury.
S. Omoto, M. Ueno, S. Mochio, T. Takai, and T. Yamashita (2010)
J. Neurosci. 30, 13045-13052
   Abstract »    Full Text »    PDF »
Guidance Molecules in Axon Regeneration.
R. J. Giger, E. R. Hollis II, and M. H. Tuszynski (2010)
Cold Spring Harb Perspect Biol 2, a001867
   Abstract »    Full Text »    PDF »
MAG and OMgp Synergize with Nogo-A to Restrict Axonal Growth and Neurological Recovery after Spinal Cord Trauma.
W. B. J. Cafferty, P. Duffy, E. Huebner, and S. M. Strittmatter (2010)
J. Neurosci. 30, 6825-6837
   Abstract »    Full Text »    PDF »
A Chemical Screen Identifies Novel Compounds That Overcome Glial-Mediated Inhibition of Neuronal Regeneration.
L. C. Usher, A. Johnstone, A. Erturk, Y. Hu, D. Strikis, I. B. Wanner, S. Moorman, J. W. Lee, J. Min, H. H. Ha, et al. (2010)
J. Neurosci. 30, 4693-4706
   Abstract »    Full Text »    PDF »
Structural Characterization of the EphA4-Ephrin-B2 Complex Reveals New Features Enabling Eph-Ephrin Binding Promiscuity.
H. Qin, R. Noberini, X. Huan, J. Shi, E. B. Pasquale, and J. Song (2010)
J. Biol. Chem. 285, 644-654
   Abstract »    Full Text »    PDF »
Rho-Associated Kinase II (ROCKII) Limits Axonal Growth after Trauma within the Adult Mouse Spinal Cord.
P. Duffy, A. Schmandke, A. Schmandke, J. Sigworth, S. Narumiya, W. B. J. Cafferty, and S. M. Strittmatter (2009)
J. Neurosci. 29, 15266-15276
   Abstract »    Full Text »    PDF »
Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation.
E. R. Hollis II, P. Jamshidi, K. Low, A. Blesch, and M. H. Tuszynski (2009)
PNAS 106, 7215-7220
   Abstract »    Full Text »    PDF »
Crystal Structure and NMR Binding Reveal That Two Small Molecule Antagonists Target the High Affinity Ephrin-binding Channel of the EphA4 Receptor.
H. Qin, J. Shi, R. Noberini, E. B. Pasquale, and J. Song (2008)
J. Biol. Chem. 283, 29473-29484
   Abstract »    Full Text »    PDF »
Small Molecules Can Selectively Inhibit Ephrin Binding to the EphA4 and EphA2 Receptors.
R. Noberini, M. Koolpe, S. Peddibhotla, R. Dahl, Y. Su, N. D. P. Cosford, G. P. Roth, and E. B. Pasquale (2008)
J. Biol. Chem. 283, 29461-29472
   Abstract »    Full Text »    PDF »
The Role of Kalirin9 in p75/Nogo Receptor-mediated RhoA Activation in Cerebellar Granule Neurons.
A. W. Harrington, Q. M. Li, C. Tep, J. B. Park, Z. He, and S. O. Yoon (2008)
J. Biol. Chem. 283, 24690-24697
   Abstract »    Full Text »    PDF »
Inactivation of Glycogen Synthase Kinase 3 Promotes Axonal Growth and Recovery in the CNS.
J. Dill, H. Wang, F. Zhou, and S. Li (2008)
J. Neurosci. 28, 8914-8928
   Abstract »    Full Text »    PDF »
Netrin-1 Is a Novel Myelin-Associated Inhibitor to Axon Growth.
K. Low, M. Culbertson, F. Bradke, M. Tessier-Lavigne, and M. H. Tuszynski (2008)
J. Neurosci. 28, 1099-1108
   Abstract »    Full Text »    PDF »
ROCK inhibition and CNTF interact on intrinsic signalling pathways and differentially regulate survival and regeneration in retinal ganglion cells.
P. Lingor, L. Tonges, N. Pieper, C. Bermel, E. Barski, V. Planchamp, and M. Bahr (2008)
Brain 131, 250-263
   Abstract »    Full Text »    PDF »
Upregulation of EphB2 and ephrin-B2 at the Optic Nerve Head of DBA/2J Glaucomatous Mice Coincides with Axon Loss.
J. Du, T. Tran, C. Fu, and D. W. Sretavan (2007)
Invest. Ophthalmol. Vis. Sci. 48, 5567-5581
   Abstract »    Full Text »    PDF »
Single Amino Acid Changes in the Nipah and Hendra Virus Attachment Glycoproteins Distinguish EphrinB2 from EphrinB3 Usage.
O. A. Negrete, D. Chu, H. C. Aguilar, and B. Lee (2007)
J. Virol. 81, 10804-10814
   Abstract »    Full Text »    PDF »
Caenorhabditis elegans neuronal regeneration is influenced by life stage, ephrin signaling, and synaptic branching.
Z. Wu, A. Ghosh-Roy, M. F. Yanik, J. Z. Zhang, Y. Jin, and A. D. Chisholm (2007)
PNAS 104, 15132-15137
   Abstract »    Full Text »    PDF »
Nonsteroidal Anti-Inflammatory Drugs Promote Axon Regeneration via RhoA Inhibition.
Q. Fu, J. Hue, and S. Li (2007)
J. Neurosci. 27, 4154-4164
   Abstract »    Full Text »    PDF »
The Nogo-Nogo Receptor Pathway Limits a Spectrum of Adult CNS Axonal Growth..
W. B. J. Cafferty and S. M. Strittmatter (2006)
J. Neurosci. 26, 12242-12250
   Abstract »    Full Text »    PDF »
Ephrin-B3 Ligand Promotes Glioma Invasion through Activation of Rac1..
M. Nakada, K. L. Drake, S. Nakada, J. A. Niska, and M. E. Berens (2006)
Cancer Res. 66, 8492-8500
   Abstract »    Full Text »    PDF »
Nogo-A-Deficient Mice Reveal Strain-Dependent Differences in Axonal Regeneration.
L. Dimou, L. Schnell, L. Montani, C. Duncan, M. Simonen, R. Schneider, T. Liebscher, M. Gullo, and M. E. Schwab (2006)
J. Neurosci. 26, 5591-5603
   Abstract »    Full Text »    PDF »
RGMa inhibition promotes axonal growth and recovery after spinal cord injury.
K. Hata, M. Fujitani, Y. Yasuda, H. Doya, T. Saito, S. Yamagishi, B. K. Mueller, and T. Yamashita (2006)
J. Cell Biol. 173, 47-58
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882