Soluble Nogo receptor down-regulates expression of neuronal Nogo-A to enhance axonal regeneration.
Nogo-A, a member of the reticulon family, is present in neurons and oligodendrocytes. Nogo-A in central nervous system (CNS) myelin prevents axonal regeneration through interaction with Nogo receptor 1, but the function of Nogo-A in neurons is less known. We found that after axonal injury, Nogo-A is increased in dorsal root ganglion (DRG) neurons unable to regenerate following a dorsal root injury or a sciatic nerve ligation-cut injury and that exposure in vitro to CNS myelin dramatically enhanced neuronal Nogo-A mRNA and protein through activation of RhoA while inhibiting neurite growth. Knocking down neuronal Nogo-A by small interfering RNA results in a marked increase of neurite outgrowth. We constructed a nonreplicating herpes simplex virus vector (QHNgSR) to express a truncated soluble fragment of Nogo receptor 1 (NgSR). NgSR released from QHNgSR prevented myelin inhibition of neurite extension by hippocampal and DRG neurons in vitro. NgSR prevents RhoA activation by myelin and decreases neuronal Nogo-A. Subcutaneous inoculation of QHNgSR to transduce DRG neurons resulted in improved regeneration of myelinated fibers in both the dorsal root and the spinal dorsal root entry zone, with concomitant improvement in sensory behavior. The results indicate that neuronal Nogo-A is an important intermediate in neurite growth dynamics and its expression is regulated by signals related to axonal injury and regeneration, that CNS myelin appears to activate signaling events that mimic axonal injury, and that NgSR released from QHNgSR may be used to improve recovery after injury.
Peng
Xiangmin
X
Department of Neurology, University of Michigan, and Ann Arbor Veterans Affairs Healthcare System, Ann Arbor, Michigan 48109, USA.
Zhou
Zhigang
Z
Hu
Jian
J
Fink
David J
DJ
Mata
Marina
M
D000818:Animals; D001369:Axons / Q000502:physiology*; D000242:Cyclic AMP / Q000494:pharmacology; D003714:Denervation; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000166:cytology / Q000293:injuries; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D009409:Nerve Crush; D009414:Nerve Growth Factors / Q000494:pharmacology; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D012584:Sciatic Nerve / Q000166:cytology / Q000293:injuries; D012995:Solubility; D013116:Spinal Cord / Q000166:cytology; D014158:Transcription, Genetic / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D009414:Nerve Growth Factors; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C000603197:Rtn4 protein, rat; C486581:Rtn4r protein, rat; D000242:Cyclic AMP; D020742:rhoA GTP-Binding Protein