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:

Fas engagement induces neurite growth through ERK activation and p35 upregulation

Nature Cell Biology volume 5, pages 118–125 (2003)Cite this article

Abstract

Fas (also known as CD95), a member of the tumour-necrosis receptor factor family of 'death receptors', can induce apoptosis or, conversely, can deliver growth stimulatory signals. Here we report that crosslinking Fas on primary sensory neurons induces neurite growth through sustained activation of the extracellular-signal regulated kinase (ERK) pathway and the consequent upregulation of p35, a mediator of neurite outgrowth. In addition, functional recovery after sciatic nerve injury is delayed in Fas-deficient lpr mice and accelerated by local administration of antibodies against Fas, which indicates that Fas engagement may contribute to nerve regeneration in vivo. Our findings define a role for Fas as an inducer of both neurite growth in vitro and accelerated recovery after nerve injury in vivo.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Fas engagement does not induce apoptosis in SH-SY5Y cells.
Figure 2: Fas induces ERK phosphorylation and p35 expression.
Figure 3: Fas engagement induces neurite outgrowth in DRG explants.
Figure 4: Fas-induced neurite growth depends on ERK activation.
Figure 5: Fas-induced neurite growth is independent of the Fas death domain.
Figure 6: Fas engagement accelerates in vivo functional recovery.

Similar content being viewed by others

References

  1. Yonehara, S., Ishii, A. & Yonehara, M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J. Exp. Med. 169, 1747–1756 (1989).

    Article  CAS  Google Scholar 

  2. Trauth, B.C. et al. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245, 301–305 (1989).

    Article  CAS  Google Scholar 

  3. Shinohara, H., Yagita, H., Ikawa, Y. & Oyaizu, N. Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase. Cancer Res. 60, 1766–1772 (2000).

    CAS  PubMed  Google Scholar 

  4. Gomez, C. et al. Low concentrations of 1-methyl-4-phenylpyridinium ion induce caspase-mediated apoptosis in human SH-SY5Y neuroblastoma cells. J. Neurosci. Res. 63, 421–428 (2001).

    Article  CAS  Google Scholar 

  5. Becher, B., D'Souza, S.D., Troutt, A.B. & Antel, J.P. Fas expression on human fetal astrocytes without susceptibility to Fas-mediated cytotoxicity. Neurosciences 84, 627–634 (1998).

    Article  CAS  Google Scholar 

  6. Raoul, C., Henderson, C.E. & Pettmann, B. Programmed cell death of embryonic motoneurons triggered through the Fas death receptor. J. Cell Biol. 147, 1049–1062 (1999).

    Article  CAS  Google Scholar 

  7. Raoul, C. et al. Motoneuron death triggered by a specific pathway downstream of Fas. Potentiation by ALS-linked SOD1 mutations. Neuron 35, 1067–1083 (2002).

    Article  CAS  Google Scholar 

  8. Matsushita, K. et al. Fas receptor and neuronal cell death after spinal cord ischemia. J. Neurosci. 20, 6879–6887 (2000).

    Article  CAS  Google Scholar 

  9. Cheema, Z.F. et al. Fas/Apo (apoptosis)-1 and associated proteins in the differentiating cerebral cortex: induction of caspase-dependent cell death and activation of NF-κB. J. Neurosci. 19, 1754–1770 (1999).

    Article  CAS  Google Scholar 

  10. Alderson, M.R. et al. Fas transduces activation signals in normal human T lymphocytes. J. Exp. Med. 178, 2231–2235 (1993).

    Article  CAS  Google Scholar 

  11. Owen-Schaub, L.B., Meterissian, S. & Ford, R.J. Fas/APO-1 expression and function on malignant cells of hematologic and non-hematologic origin. J. Immunother. 14, 234–241 (1993).

    Article  CAS  Google Scholar 

  12. Alderson, M.R. et al. Regulation of apoptosis and T cell activation by Fas-specific mAb. Int. Immunol. 6, 1799–1806 (1994).

    Article  CAS  Google Scholar 

  13. Freiberg, R.A. et al. Fas signal transduction triggers either proliferation or apoptosis in human fibroblasts. J. Invest. Dermatol. 108, 215–219 (1997).

    Article  CAS  Google Scholar 

  14. Desbarats, J., Wade, T., Wade, W.F. & Newell, M.K. Dichotomy between naïve and memory CD4+ T cell responses to Fas (CD95) engagement. Proc. Natl Acad. Sci. USA 96, 8104–8109 (1999).

    Article  CAS  Google Scholar 

  15. Desbarats, J. & Newell, M.K. Fas engagement accelerates liver regeneration after partial hepatectomy. Nature Med. 6, 920–923 (2000).

    Article  CAS  Google Scholar 

  16. Tsutsui, H. et al. Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. Immunity 11, 359–367 (1999).

    Article  CAS  Google Scholar 

  17. Nagata, S. Apoptosis by death factor. Cell 88, 355–365 (1997).

    Article  CAS  Google Scholar 

  18. Medema, J.P. et al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J. 16, 2794–2804 (1997).

    Article  CAS  Google Scholar 

  19. Irmler, M. et al. Inhibition of death receptor signals by cellular FLIP. Nature 388, 190–195 (1997).

    Article  CAS  Google Scholar 

  20. Fukunaga, K. & Miyamoto, E. Role of MAP kinase in neurons. Mol. Neurobiol. 16, 79–95 (1998).

    Article  CAS  Google Scholar 

  21. Holmstrom, T. et al. MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly. EMBO J. 19, 5418–5428 (2000).

    Article  CAS  Google Scholar 

  22. Kataoka, T. et al. The caspase-8 inhibitor FLIP promotes activation of NF-κB and ERK signaling pathways. Curr. Biol. 10, 640–648 (2000).

    Article  CAS  Google Scholar 

  23. Kury, P., Stoll, G. & Muller, H.W. Molecular mechanisms of cellular interactions in peripheral nerve regeneration. Curr. Opin. Neurobiol. 14, 635–639 (2001).

    Article  CAS  Google Scholar 

  24. Levi-Montalcini, R., Meyer, H. & Hamburger, V. In vitro experiments on the effects of mouse sarcoma 180 and 37 on the spinal and sympathetic ganglia of the chick embryo. Cancer Res. 14, 49–57 (1954).

    CAS  PubMed  Google Scholar 

  25. Lonze, B.E., Riccio, A., Cohen, S. & Ginty, D.D. Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34, 371–385 (2002).

    Article  CAS  Google Scholar 

  26. Chen, M.S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000).

    Article  CAS  Google Scholar 

  27. Ledda, F., Paratcha, G. & Ibanez, C.F. Target-derived GFRα1 as an attractive guidance signal for developing sensory and sympathetic axons via activation of Cdk5. Neuron 36, 387–401 (2002).

    Article  CAS  Google Scholar 

  28. Levi-Montalcini, R. & Angeletti, P.U. Essential role of the nerve growth factor in survival and maintenance of dissociated sensory and sympathetic embryonic nerve cells in vitro. Dev. Biol. 7, 653–659 (1963).

    Article  Google Scholar 

  29. Qian, X., Riccio, A., Zhang, Y. & Ginty, D.D. Identification and characterization of novel substrates of Trk receptors in developing neurons. Neuron 21, 1017–1029 (1998).

    Article  CAS  Google Scholar 

  30. Cowley, S., Paterson, H., Kemp, P. & Marshall, C.J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841–852 (1994).

    Article  CAS  Google Scholar 

  31. Pang, L., Sawada, T., Decker, S.J. & Saltiel, A.R. Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J. Biol. Chem. 270, 13585–13588 (1995).

    Article  CAS  Google Scholar 

  32. Harada, T., Morooka, T., Ogawa, S. & Nishida, E. ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nature Cell Biol. 3, 453–459 (2001).

    Article  CAS  Google Scholar 

  33. Nikolic, M., Dudek, H., Kwon, Y.T., Ramos, Y.F. & Tsai, L.S. The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 10, 816–825 (1996).

    Article  CAS  Google Scholar 

  34. Biedler, J.L., Roffler-Tarlov, S., Schachner, M. & Freedman, L.S. Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res. 38, 3751–3757 (1978).

    CAS  PubMed  Google Scholar 

  35. Ju, S.T. et al. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373, 345–348 (1995).

    Article  Google Scholar 

  36. Kimura, M. & Matsuzawa, A. Autoimmunity in mice bearing lpr.cg: a novel mutant gene. Int. Rev. Immunol. 11, 193–210 (1994).

    Article  CAS  Google Scholar 

  37. Chinnaiyan, A.M., O'Rourke, K., Tewari, M. & Dixit, V.M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81, 505–512 (1995).

    Article  CAS  Google Scholar 

  38. Eberstadt, M., Huang, B., Olejniczak, E.T. & Fesik, S.W. The lymphoproliferation mutation in Fas locally unfolds the Fas death domain. Nature Struct. Biol. 4, 983–985 (1997).

    Article  CAS  Google Scholar 

  39. Adachi, M., Watanabe-Fukunaga, R. & Nagata, S. Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc. Natl Acad. Sci. USA 90, 1756–1760 (1993).

    Article  CAS  Google Scholar 

  40. De Medinaceli, L., Freed, W.J. & Wyatt, R.J. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp. Neurol. 77, 634–643 (1982).

    Article  CAS  Google Scholar 

  41. Sakic, B. et al. Progressive atrophy of pyramidal neuron dendrites in autoimmune MRL-lpr mice. J. Neuroimmunol. 87, 162–170 (1998).

    Article  CAS  Google Scholar 

  42. Martin-Villalba, A. et al. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J. Neurosci. 19, 3809–3817 (1999).

    Article  CAS  Google Scholar 

  43. Newell, M.K. et al. Does the oxidative/glycolytic ratio determine proliferation or death in immune recognition? Ann. NY Acad. Sci. 887, 77–82 (1999).

    Article  CAS  Google Scholar 

  44. Wohlleben, G. et al. Regulation of Fas and FasL expression on rat Schwann cells. Glia 30, 373–381 (2000).

    Article  CAS  Google Scholar 

  45. Schwartz, M., Moalem, G., Leibowitz-Amit, R. & Cohen, I.R. Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci. 22, 295–299 (1999).

    Article  CAS  Google Scholar 

  46. Biancone, L. et al. Development of inflammatory angiogenesis by local stimulation of Fas in vivo. J. Exp. Med. 186, 147–152 (1997).

    Article  CAS  Google Scholar 

  47. Tran, S.E., Holmstrom, T.H., Ahonen, M., Kahari, V.M. & Eriksson, J.E. MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. J. Biol. Chem. 276, 16484–16490 (2001).

    Article  CAS  Google Scholar 

  48. Wilson, D., Alessandrini, A. & Budd, R. MEK1 activation rescues Jurkat T cells from Fas-induced apoptosis. Cell. Immunol. 194, 67–77 (1999).

    Article  CAS  Google Scholar 

  49. Wosik, K., Becher, B., Ezman, A., Nalbantoglu, J. & Antel, J.P. Caspase 8 expression and signaling in Fas injury-resistant human fetal astrocytes. Glia 33, 217–224 (2001).

    Article  CAS  Google Scholar 

  50. Desbarats, J., Duke, R.C. & Newell, M.K. Newly discovered role for Fas ligand in the cell-cycle arrest of CD4+ T cells. Nature Med. 4, 1377–1381 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Rogers for technical support; V. Scott for assistance with walking-track data collection; and D. D'Iusso, T. Kahawita and S. Shadvar for general laboratory assistance. This work was supported by grants from the NIH (to J.D., R.B.B. and M.K.N.), a Muscular Dystrophy Association award (to R.B.B.) and sponsored research funding from Immune Response Corporation (to M.K.N.).

Author information

Authors and Affiliations

  1. Department of Physiology, McGill University, Montréal, H3G 1Y6, Quebec, Canada

    Julie Desbarats, Manuelle Mimouni-Rongy & Jean-Sébastien Palerme

  2. Laboratory of Molecular Oncology, the Rockefeller University, New York, 10021, NY, USA

    Julie Desbarats & Raymond B. Birge

  3. Department of Biology, University of Colorado at Colorado Springs, Colorado Springs, 80918, CO, USA

    Julie Desbarats & M. Karen Newell

  4. Department of Biochemistry and Molecular Biology, New Jersey Medical School, Newark, 07103, NJ, USA

    Raymond B. Birge

  5. Departments of Neuroscience and Pathology, The Albert Einstein College of Medicine, Bronx, 10461, NY, USA

    David E. Weinstein

Authors
  1. Julie Desbarats
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raymond B. Birge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuelle Mimouni-Rongy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David E. Weinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Sébastien Palerme
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Karen Newell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julie Desbarats.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Desbarats, J., Birge, R., Mimouni-Rongy, M. et al. Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol 5, 118–125 (2003). https://doi.org/10.1038/ncb916

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb916

This article is cited by

Search

Advanced 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