Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury

This article has been updated

Abstract

Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75NTR), pro-neurotrophins induce apoptosis in cultured neurons by engaging sortilin and p75NTR in a death-signaling receptor complex. Substantial amounts of neurotrophins are secreted in pro-form in vivo, yet their physiological significance remains unclear. We generated a sortilin-deficient mouse to examine the contribution of the p75NTR/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)−/− mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75NTR-deficient (Ngfr−/−) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1−/− mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin–induced apoptotic signaling in pathological conditions, but also in specific stages of neuronal development and aging.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation of the Sort1−/− mouse.
Figure 2: Sortilin is essential for the pro-apoptotic action of pro-neurotrophins in cultured SCG neurons.
Figure 3: Developmentally regulated apoptosis of sympathetic neurons is normal in Sort1−/− mice.
Figure 4: Synthesis and accumulation of pro-neurotrophins in aged sympathetic neurons.
Figure 5: Protection against age-dependent death of sympathetic neurons in sortilin knockout mice.
Figure 6: Reduced cell death in the developing retina (E15.5) of sortilin knockout mice.
Figure 7: Sortilin expression in the motor cortex of axotomized rats.
Figure 8: Sortilin-deficiency protects injured adult corticospinal neurons from cell death.

Similar content being viewed by others

Change history

  • 22 October 2007

    changed sign

Notes

  1. *NOTE: In the version of this article initially published online, the label for the bottom panel of Figure 1b was incorrect.The label should be –/– . The error has been corrected for all versions of the article.

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Nykjaer, A., Willnow, T.E. & Petersen, C.M. p75NTR—live or let die. Curr. Opin. Neurobiol. 15, 49–57 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Brennan, C., Rivas-Plata, K. & Landis, S.C. The p75 neurotrophin receptor influences NT-3 responsiveness of sympathetic neurons in vivo. Nat. Neurosci. 2, 699–705 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Bamji, S.X. et al. The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J. Cell Biol. 140, 911–923 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Frade, J.M. & Barde, Y.A. Genetic evidence for cell death mediated by nerve growth factor and the neurotrophin receptor p75 in the developing mouse retina and spinal cord. Development 126, 683–690 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Beattie, M.S. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36, 375–386 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Harrington, A.W. et al. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc. Natl. Acad. Sci. USA 101, 6226–6230 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Casaccia-Bonnefil, P., Carter, B.D., Dobrowsky, R.T. & Chao, M.V. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383, 716–719 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Kenchappa, R.S. et al. Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons. Neuron 50, 219–232 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Yoon, S.O., Casaccia-Bonnefil, P., Carter, B. & Chao, M.V. Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. J. Neurosci. 18, 3273–3281 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee, R., Kermani, P., Teng, K.K. & Hempstead, B.L. Regulation of cell survival by secreted pro-neurotrophins. Science 294, 1945–1948 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Volosin, M. et al. Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and pro-neurotrophins. J. Neurosci. 26, 7756–7766 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bruno, M.A. & Cuello, A.C. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor and its degradation by a protease cascade. Proc. Natl. Acad. Sci. USA 103, 6735–6740 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen, Z.Y. et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J. Neurosci. 24, 4401–4411 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Domeniconi, M., Hempstead, B.L. & Chao, M.V. Pro-NGF secreted by astrocytes promotes motor neuron cell death. Mol. Cell. Neurosci. 34, 271–279 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Casademunt, E. et al. The zinc finger protein NRIF interacts with the neurotrophin receptor p75(NTR) and participates in programmed cell death. EMBO J. 18, 6050–6061 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Linggi, M.S. et al. Neurotrophin receptor interacting factor (NRIF) is an essential mediator of apoptotic signaling by the p75 neurotrophin receptor. J. Biol. Chem. 280, 13801–13808 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Majdan, M. et al. Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis. J. Neurosci. 17, 6988–6998 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peng, S., Wuu, J., Mufson, E.J. & Fahnestock, M. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease. J. Neuropathol. Exp. Neurol. 63, 641–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Fahnestock, M., Michalski, B., Xu, B. & Coughlin, M.D. The precursor pro–nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease. Mol. Cell. Neurosci. 18, 210–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Kumar, A. et al. Increased pro–nerve growth factor and p75 neurotrophin receptor levels in developing hypothyroid rat cerebral cortex are associated with enhanced apoptosis. Endocrinology 147, 4893–4903 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. Rabizadeh, S. et al. Induction of apoptosis by the low-affinity NGF receptor. Science 261, 345–348 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Majdan, M., Walsh, G.S., Aloyz, R. & Miller, F.D. TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal. J. Cell Biol. 155, 1275–1285 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Andrews, T.J. & Cowen, T. Nerve growth factor enhances the dendritic arborization of sympathetic ganglion cells undergoing atrophy in aged rats. J. Neurocytol. 23, 234–241 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Gatzinsky, K.P., Thrasivoulou, C., Campioni-Noack, M., Underwood, C. & Cowen, T. The role of NGF uptake in selective vulnerability to cell death in ageing sympathetic neurons. Eur. J. Neurosci. 20, 2848–2856 (2004).

    Article  PubMed  Google Scholar 

  29. Schmidt, R.E., Beaudet, L., Plurad, S.B., Snider, W.D. & Ruit, K.G. Pathologic alterations in pre- and postsynaptic elements in aged mouse sympathetic ganglia. J. Neurocytol. 24, 189–206 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Glebova, N.O. & Ginty, D.D. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J. Neurosci. 24, 743–751 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, K.F., Bachman, K., Landis, S. & Jaenisch, R. Dependence on p75 for innervation of some sympathetic targets. Science 263, 1447–1449 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. Harada, C. et al. Effect of p75NTR on the regulation of naturally occurring cell death and retinal ganglion cell number in the mouse eye. Dev. Biol. 290, 57–65 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Frade, J.M. & Barde, Y.A. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 35–41 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang, E.J. & Reichardt, L.F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Glebova, N.O. & Ginty, D.D. Growth and survival signals controlling sympathetic nervous system development. Annu. Rev. Neurosci. 28, 191–222 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Lee, K.F., Davies, A.M. & Jaenisch, R. p75-deficient embryonic dorsal root sensory and neonatal sympathetic neurons display a decreased sensitivity to NGF. Development 120, 1027–1033 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Gonzalez-Hoyuela, M., Barbas, J.A. & Rodriguez-Tebar, A. The autoregulation of retinal ganglion cell number. Development 128, 117–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Chakrabarti, S., Sima, A.A., Lee, J., Brachet, P. & Dicou, E. Nerve growth factor (NGF), proNGF and NGF receptor-like immunoreactivity in BB rat retina. Brain Res. 523, 11–15 (1990).

    Article  CAS  PubMed  Google Scholar 

  41. Bierl, M.A. & Isaacson, L.G. Increased NGF proforms in aged sympathetic neurons and their targets. Neurobiol. Aging 28, 122–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Hasan, W., Pedchenko, T., Krizsan-Agbas, D., Baum, L. & Smith, P.G. Sympathetic neurons synthesize and secrete pro-nerve growth factor protein. J. Neurobiol. 57, 38–53 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Heumann, R., Korsching, S., Scott, J. & Thoenen, H. Relationship between levels of nerve growth factor (NGF) and its messenger RNA in sympathetic ganglia and peripheral target tissues. EMBO J. 3, 3183–3189 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Bonatz, H., Rohrig, S., Mestres, P., Meyer, M. & Giehl, K.M. An axotomy model for the induction of death of rat and mouse corticospinal neurons in vivo. J. Neurosci. Methods 100, 105–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Giehl, K.M. & Tetzlaff, W. BDNF and NT-3, but not NGF, prevent axotomy-induced death of rat corticospinal neurons in vivo. Eur. J. Neurosci. 8, 1167–1175 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Giehl, K.M. et al. Endogenous brain-derived neurotrophic factor and neurotrophin-3 antagonistically regulate survival of axotomized corticospinal neurons in vivo. J. Neurosci. 21, 3492–3502 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nyengaard, J.R. & Gundersen, H.J.G. The isector: a simple and direct method for generating isotropic, uniform random sections from small specimens. J. Microsc. 165, 427–431 (1991).

    Article  Google Scholar 

  49. Dorph-Petersen, K.A., Nyengaard, J.R. & Gundersen, H.J. Tissue shrinkage and unbiased stereological estimation of particle number and size. J. Microsc. 204, 232–246 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Jensen, E.B. & Gundersen, H.J. The rotator. J. Microsc. 171, 35–44 (1993).

    Article  Google Scholar 

Download references

Acknowledgements

We are grateful to B. Lu and G. Nagappan for providing hippocampal extracts from wild-type and BDNF knockout mice, F. Lee and P. Madsen for sharing expression constructs and P. Dan and Alomone Labs for recombinant mouse pro-BDNF. We thank B. Vestergaard, D. Wilhardt Joergensen, H. Andersen and M. Lundorf for excellent technical assistance. This work was supported by grants from the Danish Medical Research Council (A.N.), the Lundbeck Foundation (A.N., J.R.N. and C.M.P.), the Elvira and Rasmus Riisforts Foundation (A.N.), the Deutsche Forschungsgemeinschaft (G.R.L. and T.E.W.) and the US National Institutes of Health (NS30687, B.L.H).

Author information

Authors and Affiliations

Authors

Contributions

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

Corresponding authors

Correspondence to Thomas E Willnow or Anders Nykjaer.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Methods (PDF 4633 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jansen, P., Giehl, K., Nyengaard, J. et al. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci 10, 1449–1457 (2007). https://doi.org/10.1038/nn2000

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn2000

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing