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Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling

Nature Neuroscience volume 14, pages 54–61 (2011)Cite this article

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An Erratum to this article was published on 26 August 2011

This article has been updated

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 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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Figure 1: Sortilin interacts with Trk receptors.
Figure 2: Sortilin facilitates anterograde neuronal Trk trafficking.
Figure 3: Sortilin facilitates Trk signaling in neurons.
Figure 4: Aberrant gait and peripheral neuropathy in sortilin and p75NTR double knockout mice.
Figure 5: Loss of sortilin aggravates TrkC and TrkB phenotypes in p75NTR knockout mice.
Figure 6: Sortilin deficiency aggravates TrkA phenotypes in p75NTR knockout mice.
Figure 7: Absent sortilin expression induces TrkA phenotypes in Ntrk1+/− mice.

Change history

  • 14 January 2011

    In the version of this article initially published, the right-hand panel of Figure 2f was inadvertently replaced by Figure 7b. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Medical Biochemistry, The Lundbeck Foundation Research Center MIND, Aarhus University, Aarhus, Denmark

    Christian B Vaegter, Pernille Jansen, Simon Glerup, Sune Skeldal, Mads Kjolby, Mette Richner & Anders Nykjaer

  2. The Lundbeck Foundation Research Center MIND, Stereology and Electron Microscopy Laboratory, Aarhus University, Aarhus, Denmark

    Anja W Fjorback & Jens R Nyengaard

  3. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Bettina Erdmann, Gary R Lewin & Thomas E Willnow

  4. Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA

    Lino Tessarollo

  5. Kimmel Center at Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA

    Moses V Chao

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Contributions

C.B.V., P.J., A.W.F., S.G., S.S., M.R., M.K. and B.E. conducted the experiments. J.R.N., L.T., G.R.L., T.E.W. and M.V.C. provided reagents and scientific input. C.B.V. and A.N. designed the experiments and evaluated the data, and C.B.V. and A.N. wrote the manuscript.

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Correspondence to Christian B Vaegter or Anders Nykjaer.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 443 kb)

Supplementary Video 1

Live cell imaging of a WT DRG neuron transfected with EGFP-TrkA (AVI 807 kb)

Supplementary Video 2

Live cell imaging of a Sort1−/− DRG neuron transfected with EGFP-TrkA (AVI 1617 kb)

Supplementary Video 3

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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