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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
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
Similar content being viewed by others
Change history
22 October 2007
changed sign
Notes
*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
Chao, M.V. Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat. Rev. Neurosci. 4, 299–309 (2003).
Nykjaer, A., Willnow, T.E. & Petersen, C.M. p75NTR—live or let die. Curr. Opin. Neurobiol. 15, 49–57 (2005).
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).
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).
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).
Beattie, M.S. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36, 375–386 (2002).
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).
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).
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).
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).
Lee, R., Kermani, P., Teng, K.K. & Hempstead, B.L. Regulation of cell survival by secreted pro-neurotrophins. Science 294, 1945–1948 (2001).
Nykjaer, A. et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843–848 (2004).
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).
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).
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).
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).
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).
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).
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).
Majdan, M. et al. Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis. J. Neurosci. 17, 6988–6998 (1997).
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).
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).
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).
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).
Rabizadeh, S. et al. Induction of apoptosis by the low-affinity NGF receptor. Science 261, 345–348 (1993).
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).
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).
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).
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).
Glebova, N.O. & Ginty, D.D. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J. Neurosci. 24, 743–751 (2004).
Lee, K.F., Bachman, K., Landis, S. & Jaenisch, R. Dependence on p75 for innervation of some sympathetic targets. Science 263, 1447–1449 (1994).
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).
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).
Frade, J.M. & Barde, Y.A. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 35–41 (1998).
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).
Huang, E.J. & Reichardt, L.F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).
Glebova, N.O. & Ginty, D.D. Growth and survival signals controlling sympathetic nervous system development. Annu. Rev. Neurosci. 28, 191–222 (2005).
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).
Gonzalez-Hoyuela, M., Barbas, J.A. & Rodriguez-Tebar, A. The autoregulation of retinal ganglion cell number. Development 128, 117–124 (2001).
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).
Bierl, M.A. & Isaacson, L.G. Increased NGF proforms in aged sympathetic neurons and their targets. Neurobiol. Aging 28, 122–134 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
Jensen, E.B. & Gundersen, H.J. The rotator. J. Microsc. 171, 35–44 (1993).
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
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
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–4 and Methods (PDF 4633 kb)
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn2000
This article is cited by
-
Gancao Nourishing-Yin decoction combined with methotrexate in treatment of aging CIA mice: a study based on DIA proteomic analysis
Chinese Medicine (2023)
-
Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia
Journal of Translational Medicine (2023)
-
METH exposure alters sperm DNA methylation in F0 mice and mPFC transcriptome in male F1 mice
Psychopharmacology (2023)
-
Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease
Molecular Neurodegeneration (2022)
-
The emerging role of furin in neurodegenerative and neuropsychiatric diseases
Translational Neurodegeneration (2022)