Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo.
Axon regeneration failure in the adult mammalian CNS is attributed in part to the inhibitory nature of CNS myelin. Three myelin-associated, structurally distinct proteins, Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein, have been implicated in this inhibition. Neuronal Nogo receptor (NgR) binds to each of the three inhibitors and has been proposed to mediate their inhibitory signals by complexing with a signal-transducing coreceptor, the neurotrophin receptor p75(NTR). To assess the contribution of NgR to mediating myelin inhibitory signals and regeneration failure in vivo, we generated and characterized NgR-deficient mice. Nogo transcripts are up-regulated in NgR mutants, indicating that NgR regulates Nogo in vivo. However, neurite outgrowth from NgR-deficient postnatal dorsal root ganglion or cerebellar granule neurons is inhibited by myelin and by a Nogo-66 substrate to the same extent as is from wild-type neurons, whereas p75(NTR)-deficient neurons are less inhibited. The NgR ligand-binding domain promotes neurite outgrowth on Nogo-66, regardless of the genotype of the neurons, indicating that the NgR ligand-binding domain can act independent of NgR. Thus, NgR is not essential for mediating inhibitory signals from CNS myelin, at least in the neurons tested, whereas p75(NTR) plays a central role in this response. Neither NgR-nor p75(NTR)-deficient mice showed enhanced regeneration of corticospinal tract axons in comparison with wild-type controls after spinal dorsal hemisection. Our results thus fail to support a central role for NgR in axonal growth inhibition in vitro or in corticospinal tract regeneration block in vivo.
Zheng
Binhai
B
Department of Biological Sciences, Program in Neurosciences, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Atwal
Jasvinder
J
Ho
Carole
C
Case
Lauren
L
He
Xiao-lin
XL
Garcia
K Christopher
KC
Steward
Oswald
O
Tessier-Lavigne
Marc
M
D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000502:physiology*; D009416:Nerve Regeneration; D016501:Neurites / Q000502:physiology*; D000070798:Nogo Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D018000:Receptors, Peptide / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*
D009185:Myelin Proteins; D000070798:Nogo Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D018000:Receptors, Peptide; C000603201:Rtn4 protein, mouse