PirB is a functional receptor for myelin inhibitors of axonal regeneration.
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.
Atwal
Jasvinder K
JK
Neurodegeneration Labs and Research Drug Discovery, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Pinkston-Gosse
Julie
J
Syken
Josh
J
Stawicki
Scott
S
Wu
Yan
Y
Shatz
Carla
C
Tessier-Lavigne
Marc
M
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000166:cytology; D020439:Growth Cones / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D009416:Nerve Regeneration; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism
D058851:GPI-Linked Proteins; C104739:Mag protein, mouse; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; C560529:Omg protein, mouse; C105949:Pirb protein, mouse; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C000603201:Rtn4 protein, mouse; C419790:Rtn4r protein, mouse