title: Neurotrophic actions initiated by proNGF in adult sensory neurons may require peri-somatic glia to drive local cleavage to NGF.
abstract: The nerve growth factor (NGF) precursor, proNGF, is implicated in various neuropathological states. ProNGF signals apoptosis by forming a complex with the receptors p75 and sortilin, however, it can also induce neurite growth, proposed to be mediated by the receptor of mature NGF, tyrosine kinase receptor A (TrkA). The way in which these dual effects occur in adult neurons is unclear. We investigated the neurotrophic effects of proNGF on peptidergic sensory neurons isolated from adult mouse dorsal root ganglia and found that proNGF stimulated neurite extension and branching, requiring p75, sortilin and TrkA. Neurite growth rarely occurred in sortilin-expressing neurons but was commonly observed in TrkA-positive, sortilin-negative neurons that associated closely with sortilin-positive glia. ProNGF was unable to induce local trophic effects at growth cones where sortilin-positive glia was absent. We propose that in adult sensory neurons the neurotrophic response to proNGF is mediated by NGF and TrkA, and that peri-somatic glia may participate in sortilin- and p-75 dependent cleavage of proNGF. The potential ability of local glial cells to provide a targeted supply of NGF may provide an important way to promote trophic (rather than apoptotic) outcomes under conditions where regeneration or sprouting is required.
authors.affiliation: Pain Management Research Institute and Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Adrianna
authors.initials: A
authors.lastname: Kalous
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nangle
authors.forename: Agustin
authors.initials: A
authors.lastname: Anastasia
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.forename: Janet R
authors.initials: JR
authors.lastname: Keast
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009457:Neuroglia / Q000502:physiology*; D011498:Protein Precursors / Q000494:pharmacology*; D020917:Receptor, trkA / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000276:immunology; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000906:Antibodies; D015740:Calcitonin Gene-Related Peptide; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D026121:Indole Alkaloids; D020932:Nerve Growth Factor; D011498:Protein Precursors; D020917:Receptor, trkA; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D000099183:Sortilin; C489226:pro-nerve growth factor, mouse; C049985:staurosporine aglycone