title: Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling.
abstract: Binding of target-derived neurotrophins to Trk receptors at nerve terminals is required to stimulate neuronal survival, differentiation, innervation and synaptic plasticity. The distance between the soma and nerve terminal is great, making efficient anterograde Trk transport critical for Trk synaptic translocation and signaling. The mechanism responsible for this trafficking remains poorly understood. Here we show that the sorting receptor sortilin interacts with TrkA, TrkB and TrkC and enables their anterograde axonal transport, thereby enhancing neurotrophin signaling. Cultured DRG neurons lacking sortilin showed blunted MAP kinase signaling and reduced neurite outgrowth upon stimulation with NGF. Moreover, deficiency for sortilin markedly aggravated TrkA, TrkB and TrkC phenotypes present in p75(NTR) knockouts, and resulted in increased embryonic lethality and sympathetic neuropathy in mice heterozygous for TrkA. Our findings demonstrate a role for sortilin as an anterograde trafficking receptor for Trk and a positive modulator of neurotrophin-induced neuronal survival.
authors.affiliation: The Lundbeck Foundation Research Center MIND, Department of Medical Biochemistry, Aarhus University, Aarhus, Denmark.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Vaegter
authors.forename: Pernille
authors.initials: P
authors.lastname: Jansen
authors.forename: Anja W
authors.initials: AW
authors.lastname: Fjorback
authors.forename: Simon
authors.initials: S
authors.lastname: Glerup
authors.forename: Sune
authors.initials: S
authors.lastname: Skeldal
authors.forename: Mads
authors.initials: M
authors.lastname: Kjolby
authors.forename: Mette
authors.initials: M
authors.lastname: Richner
authors.forename: Bettina
authors.initials: B
authors.lastname: Erdmann
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Gary R
authors.initials: GR
authors.lastname: Lewin
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology*; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000378:metabolism; D004622:Embryo, Mammalian / Q000473:pathology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000378:metabolism / Q000473:pathology; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020932:Nerve Growth Factor; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin