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Science 7 November 2008:
Vol. 322. no. 5903, pp. 967 - 970
DOI: 10.1126/science.1161151
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Reports

PirB is a Functional Receptor for Myelin Inhibitors of Axonal Regeneration

Jasvinder K. Atwal,1* Julie Pinkston-Gosse,1* Josh Syken,2 Scott Stawicki,3 Yan Wu,3 Carla Shatz,2,4 Marc Tessier-Lavigne1{dagger}

A major barrier to regenerating axons after injury in the mammalian central nervous system is an unfavorable milieu. Three proteins found in myelin—Nogo, MAG, and OMgp—inhibit axon regeneration in vitro and bind to the glycosylphosphatidylinositol-anchored Nogo receptor (NgR). However, genetic deletion of NgR has only a modest disinhibitory effect, suggesting that other binding receptors for these molecules probably exist. With the use of expression cloning, we have found that paired immunoglobulin-like receptor B (PirB), which has been implicated in nervous system plasticity, is a high-affinity receptor for Nogo, MAG, and OMgp. Interfering with PirB activity, either with antibodies or genetically, partially rescues neurite inhibition by Nogo66, MAG, OMgp, and myelin in cultured neurons. Blocking both PirB and NgR activities leads to near-complete release from myelin inhibition. Our results implicate PirB in mediating regeneration block, identify PirB as a potential target for axon regeneration therapies, and provide an explanation for the similar enhancements of visual system plasticity in PirB and NgR knockout mice.

1 Neurodegeneration Labs and Research Drug Discovery, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2 Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
3 Department of Antibody Engineering, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
4 Bio-X Program, Stanford University, James H. Clark Center, 318 Campus Drive, Stanford, CA 94305, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: marctl{at}gene.com

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Science. ISSN 0036-8075 (print), 1095-9203 (online)