title: Suppression of neurite outgrowth by high-dose nerve growth factor is independent of functional p75NTR receptors.
abstract: We have previously demonstrated that high concentrations of nerve growth factor suppress neurite outgrowth from sensory neurons. Inhibition could be mediated by either the p75NTR or TrkA receptor. We used a functional block of p75NTR by REX antibody in rat dorsal root ganglion neurons and dorsal root ganglion cultures from p75NTR knockout mice. In both systems, high-dose NGF inhibited neurite outgrowth, implying that p75NTR is not involved in suppression of neurite outgrowth. Confocal images of dissociated dorsal root ganglion neurons exposed to fluorescence-tagged NGF showed ligand internalization. Radioligand binding indicated disappearance of high-affinity binding sites from the surface of dorsal root ganglia after treatment with 200 ng/ml NGF for 1 h. Downstream signaling showed sustained hyperphosphorylation of MAPK (Erk(1-2)) but not of SNT or Akt. High-dose NGF may induce cytoplasmic relocation of the receptor TrkA and axonal growth arrest independently of p75NTR.
authors.affiliation: Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Conti
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Miller
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Windebank
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics
chemical_list: D000906:Antibodies; D008024:Ligands; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA