title: TNFα reverse signaling promotes sympathetic axon growth and target innervation.
abstract: Reverse signaling via members of the tumor necrosis factor (TNF) superfamily controls multiple aspects of immune function. Here we document TNFα reverse signaling in the nervous system to our knowledge for the first time and show that it has a crucial role in establishing sympathetic innervation. During postnatal development, sympathetic axons express TNFα as they grow and branch in their target tissues, which in turn express TNF receptor 1 (TNFR1). In culture, soluble forms of TNFR1 act directly on postnatal sympathetic axons to promote growth and branching by a mechanism that depends on membrane-integrated TNFα and on downstream activation of ERK. Sympathetic innervation density is substantially lower in several tissues in postnatal and adult mice lacking either TNFα or TNFR1. These findings reveal that target-derived TNFR1 acts as a reverse-signaling ligand for membrane-integrated TNFα to promote growth and branching of sympathetic axons.
authors.affiliation: Division of Molecular Biosciences, School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kisiswa
authors.forename: Catarina
authors.initials: C
authors.lastname: Osório
authors.forename: Clara
authors.initials: C
authors.lastname: Erice
authors.forename: Thomas
authors.initials: T
authors.lastname: Vizard
authors.forename: Sean
authors.initials: S
authors.lastname: Wyatt
authors.forename: Alun M
authors.initials: AM
authors.lastname: Davies
mesh_terms: D051722:ADAM Proteins / Q000494:pharmacology; D000072198:ADAM17 Protein; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009412:Nerve Fibers / Q000502:physiology*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000166:cytology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D004533:Egtazic Acid; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium