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 p75NTR 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.
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We thank L. Reichardt (University of California, San Francisco) for the TrkA antibody. The ImageJ KymoToolBox plug-in was kindly provided by F. Cordelières (Université Paris-Sud Orsay), and the NeuriteTracer plug-in by M. Pool (Rue University). This work was supported by the Lundbeck Foundation, The Danish Medical Research Council, Elvira and Rasmus Rissforts Foundation, MEMORIES (European Union, Framework Programme 6), US National Institutes of Health (NS21072, AG025970 and HD23315), the Deutsche Forschungsgemeinschaft, Danish Council for Strategic Research, and Center for Stochastic Geometry and Advanced Bioimaging (Villum Foundation).
The authors declare no competing financial interests.
Supplementary Figures 1–7 (PDF 443 kb)
Live cell imaging of a WT DRG neuron transfected with EGFP-TrkA (AVI 807 kb)
Live cell imaging of a Sort1−/− DRG neuron transfected with EGFP-TrkA (AVI 1617 kb)
Characteristic waddling gate in sortilin and p75NTR double knockout mouse (AVI 458 kb)
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Vaegter, C., Jansen, P., Fjorback, A. et al. Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat Neurosci 14, 54–61 (2011). https://doi.org/10.1038/nn.2689
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