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PNAS 102 (30): 10694-10699

Copyright © 2005 by the National Academy of Sciences.


NEUROSCIENCE

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}utsouthwestern.edu.

© 2005 by The National Academy of Sciences of the USA


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