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

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.

References

  1. 1

    Chao, M.V. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat. Rev. Neurosci. 4, 299–309 (2003).

    CAS  Google Scholar 

  2. 2

    Hirokawa, N., Noda, Y., Tanaka, Y. & Niwa, S. Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682–696 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Hirokawa, N. & Takemura, R. Molecular motors and mechanisms of directional transport in neurons. Nat. Rev. Neurosci. 6, 201–214 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Arimura, N. et al. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev. Cell 16, 675–686 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Willnow, T.E., Petersen, C.M. & Nykjaer, A. VPS10P-domain receptors—regulators of neuronal viability and function. Nat. Rev. Neurosci. 9, 899–909 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Nielsen, M.S. et al. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J. 20, 2180–2190 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Petersen, C.M. et al. Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J. Biol. Chem. 272, 3599–3605 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Sarret, P. et al. Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system. J. Comp. Neurol. 461, 483–505 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Chen, Z.Y. et al. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J. Neurosci. 25, 6156–6166 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Quistgaard, E.M. et al. Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain. Nat. Struct. Mol. Biol. 16, 96–98 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Munck Petersen, C. et al. Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding. EMBO J. 18, 595–604 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Nykjaer, A. et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843–848 (2004).

    CAS  Google Scholar 

  13. 13

    Teng, H.K. et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 25, 5455–5463 (2005).

    CAS  Google Scholar 

  14. 14

    Martin-Zanca, D., Oskam, R., Mitra, G., Copeland, T. & Barbacid, M. Molecular and biochemical characterization of the human trk proto-oncogene. Mol. Cell. Biol. 9, 24–33 (1989).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Runeberg-Roos, P. & Saarma, M. Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases. Ann. Med. 39, 572–580 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Gomes, R.A., Hampton, C., El-Sabeawy, F., Sabo, S.L. & McAllister, A.K. The dynamic distribution of TrkB receptors before, during, and after synapse formation between cortical neurons. J. Neurosci. 26, 11487–11500 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Reichardt, L.F. Neurotrophin-regulated signalling pathways. Phil. Trans. R. Soc. Lond. B 361, 1545–1564 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Russell, F.D., Koishi, K., Jiang, Y. & McLennan, I.S. Anterograde axonal transport of glial cell line-derived neurotrophic factor and its receptors in rat hypoglossal nerve. Neuroscience 97, 575–580 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Thang, S.H., Kobayashi, M. & Matsuoka, I. Regulation of glial cell line-derived neurotrophic factor responsiveness in developing rat sympathetic neurons by retinoic acid and bone morphogenetic protein-2. J. Neurosci. 20, 2917–2925 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Lee, K.F. et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–749 (1992).

    CAS  Article  Google Scholar 

  21. 21

    Ernfors, P., Lee, K.F., Kucera, J. & Jaenisch, R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 77, 503–512 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Klein, R. et al. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75, 113–122 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Minichiello, L. et al. Differential effects of combined trk receptor mutations on dorsal root ganglion and inner ear sensory neurons. Development 121, 4067–4075 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Bergmann, I. et al. Analysis of cutaneous sensory neurons in transgenic mice lacking the low affinity neurotrophin receptor p75. Eur. J. Neurosci. 9, 18–28 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Arnett, M.G., Ryals, J.M. & Wright, D.E. Pro-NGF, sortilin, and p75NTR: potential mediators of injury-induced apoptosis in the mouse dorsal root ganglion. Brain Res. 1183, 32–42 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Klein, R. et al. Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Nature 368, 249–251 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Fariñas, I., Jones, K.R., Backus, C., Wang, X.Y. & Reichardt, L.F. Severe sensory and sympathetic deficits in mice lacking neurotrophin-3. Nature 369, 658–661 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Carroll, P., Lewin, G.R., Koltzenburg, M., Toyka, K.V. & Thoenen, H. A role for BDNF in mechanosensation. Nat. Neurosci. 1, 42–46 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Perez-Pinera, P. et al. Characterization of sensory deficits in TrkB knockout mice. Neurosci. Lett. 433, 43–47 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Chuang, H.H. et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957–962 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Silos-Santiago, I. et al. Non-TrkA-expressing small DRG neurons are lost in TrkA deficient mice. J. Neurosci. 15, 5929–5942 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Coderre, T.J., Grimes, R.W. & Melzack, R. Deafferentation and chronic pain in animals: an evaluation of evidence suggesting autotomy is related to pain. Pain 26, 61–84 (1986).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Smeyne, R.J. et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 368, 246–249 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Jansen, P. et al. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat. Neurosci. 10, 1449–1457 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Mu, X., Silos-Santiago, I., Carroll, S.L. & Snider, W.D. Neurotrophin receptor genes are expressed in distinct patterns in developing dorsal root ganglia. J. Neurosci. 13, 4029–4041 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Hermans-Borgmeyer, I., Hermey, G., Nykjaer, A. & Schaller, C. Expression of the 100-kDa neurotensin receptor sortilin during mouse embryonal development. Brain Res. Mol. Brain Res. 65, 216–219 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Horton, A.C. & Ehlers, M.D. Neuronal polarity and trafficking. Neuron 40, 277–295 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Merianda, T.T. et al. A functional equivalent of endoplasmic reticulum and Golgi in axons for secretion of locally synthesized proteins. Mol. Cell. Neurosci. 40, 128–142 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Kamal, A., Almenar-Queralt, A., LeBlanc, J.F., Roberts, E.A. & Goldstein, L.S. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414, 643–648 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Kjolby, M. et al. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 12, 213–223 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Jenkins, P.M., Zhang, L., Thomas, G. & Martens, J.R. PACS-1 mediates phosphorylation-dependent ciliary trafficking of the cyclic-nucleotide-gated channel in olfactory sensory neurons. J. Neurosci. 29, 10541–10551 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Ascaño, M., Richmond, A., Borden, P. & Kuruvilla, R. Axonal targeting of Trk receptors via transcytosis regulates sensitivity to neurotrophin responses. J. Neurosci. 29, 11674–11685 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Wallrabe, H., Elangovan, M., Burchard, A., Periasamy, A. & Barroso, M. Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes. Biophys. J. 85, 559–571 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Blackstone, C.D. et al. Biochemical characterization and localization of a non-N-methyl-D-aspartate glutamate receptor in rat brain. J. Neurochem. 58, 1118–1126 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Huber, L.J. & Chao, M.V. Mesenchymal and neuronal cell expression of the p75 neurotrophin receptor gene occur by different mechanisms. Dev. Biol. 167, 227–238 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Chen, C.L. et al. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron 49, 365–377 (2006).

    CAS  Article  Google Scholar 

  47. 47

    Holmes, F.E. et al. Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity. Proc. Natl. Acad. Sci. USA 97, 11563–11568 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Zwick, M. et al. Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. J. Neurosci. 22, 4057–4065 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Wetzel, C. et al. A stomatin-domain protein essential for touch sensation in the mouse. Nature 445, 206–209 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Sokoloff, A.J., Li, H. & Burkholder, T.J. Limited expression of slow tonic myosin heavy chain in human cranial muscles. Muscle Nerve 36, 183–189 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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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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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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