title: Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors.
abstract: RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfrα2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfrα2 null mice display comparable early central projection deficits, but Gfrα2 null RA mechanoreceptors recover later. Loss of Gfrα1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfrα1;Gfrα2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRα1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling.
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Fleming
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Vysochan
authors.affiliation: Molecules - Signals - Development, Max Planck Institute of Neurobiology, Martinsried, Germany.
authors.forename: Sόnia
authors.initials: S
authors.lastname: Paixão
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Niu
authors.affiliation: Molecules - Signals - Development, Max Planck Institute of Neurobiology, Martinsried, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
authors.affiliation: Parkinson's Disease and Movement Disorder Center of Maryland, Elkridge, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Savitt
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
authors.forename: Wenqin
authors.initials: W
authors.lastname: Luo
mesh_terms: D000818:Animals; D002470:Cell Survival; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000172:deficiency / Q000235:genetics*; D008465:Mechanoreceptors / Q000166:cytology / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D051101:Neurturin / Q000172:deficiency / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000172:deficiency / Q000235:genetics*
chemical_list: C494988:Gfra1 protein, mouse; C494991:Gfra2 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051101:Neurturin; C495056:Nrtn protein, mouse; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse
keywords: DRG neuron development; RET signaling; cis and trans activation; developmental biology; mouse; neuroscience; neurotrophins; stem cells
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