title: TNF-α/TNFR1 signaling is required for the development and function of primary nociceptors.
abstract: Primary nociceptors relay painful touch information from the periphery to the spinal cord. Although it is established that signals generated by receptor tyrosine kinases TrkA and Ret coordinate the development of distinct nociceptive circuits, mechanisms modulating TrkA or Ret pathways in developing nociceptors are unknown. We have identified tumor necrosis factor (TNF) receptor 1 (TNFR1) as a critical modifier of TrkA and Ret signaling in peptidergic and nonpeptidergic nociceptors. Specifically, TrkA+ peptidergic nociceptors require TNF-α-TNFR1 forward signaling to suppress nerve growth factor (NGF)-mediated neurite growth, survival, excitability, and differentiation. Conversely, TNFR1-TNF-α reverse signaling augments the neurite growth and excitability of Ret+ nonpeptidergic nociceptors. The developmental and functional nociceptive defects associated with loss of TNFR1 signaling manifest behaviorally as lower pain thresholds caused by increased sensitivity to NGF. Thus, TNFR1 exerts a dual role in nociceptor information processing by suppressing TrkA and enhancing Ret signaling in peptidergic and nonpeptidergic nociceptors, respectively.
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wheeler
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Heffner
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Suemin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Espy
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Spano
authors.affiliation: Department of Biology, James Madison University, Harrisonburg, VA 22807, USA.
authors.forename: Corey L
authors.initials: CL
authors.lastname: Cleland
authors.affiliation: Department of Biology, University of Virginia, Charlottesville, VA 22903, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA. Electronic address: deppmann@virginia.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Deppmann
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D009619:Nociceptors / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods*; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051096:Proto-Oncogene Proteins c-ret; D020917:Receptor, trkA; C494999:Ret protein, mouse