Suppression of neurite outgrowth by high-dose nerve growth factor is independent of functional p75NTR receptors.
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.
Conti
Anna M
AM
Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA.
Brimijoin
Stephen
S
Miller
Laurence J
LJ
Windebank
Anthony J
AJ
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
D000906:Antibodies; D008024:Ligands; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA