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Shc signaling in differentiating neural progenitor cells

Abstract

Previously we found that the availability of ShcA adapter is maximal in neural stem cells but that it is absent in mature neurons. Here we report that ShcC, unlike ShcA, is not present in neural stem/progenitor cells, but is expressed after cessation of their division and becomes selectively enriched in mature neurons. Analyses of its activity in differentiating neural stem/progenitor cells revealed that ShcC positively affects their viability and neuronal maturation via recruitment of the PI3K-Akt-Bad pathway and persistent activation of the MAPK pathway. We suggest that the switch from ShcA to ShcC modifies the responsiveness of neural stem/progenitor cells to extracellular stimuli, generating proliferation (with ShcA) or survival/differentiation (with ShcC).

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Figure 1: ShcC replaces ShcA in maturing CNS neurons.
Figure 2: ShcA and ShcC expression and activation in neural progenitor cells.
Figure 3: ShcC increases survival and differentiation of neural progenitors.
Figure 4: Manipulation of ShcC levels and function affects survival and neurite elongation of primary neurons.
Figure 5: ShcC enhances viability and neuronal differentiation of conditionally immortalized neural progenitor cells.
Figure 6: ShcC modulates Akt and p42Erk2/p44Erk1 activation and Bad phosphorylation.

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References

  1. McKay, R. D. G. Stem-like cells in the central nervous system. Science 276, 66–71 (1997).

    Article  CAS  Google Scholar 

  2. Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    Article  CAS  Google Scholar 

  3. Cattaneo, E. & Pelicci, P. G. Emerging roles for SH2/PTB-containing Shc adapter proteins in the developing mammalian brain. Trends Neurosci. 21, 476–481 (1998).

    Article  CAS  Google Scholar 

  4. Segal, R. A. & Greenberg, M. E. Intracellular signalling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 19, 463–489 (1996).

    Article  CAS  Google Scholar 

  5. Pelicci, G. et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70, 93–104 (1992).

    Article  CAS  Google Scholar 

  6. Pawson, T. & Scott, J. D. Signaling through scaffold, anchoring, and adapter proteins. Science 278, 2075–2080 (1997).

    Article  CAS  Google Scholar 

  7. Lai, K. M. V. & Pawson, T. The ShcA phosphotyrosine docking protein sensitizes cardiovascular signaling in the mouse embryo. Genes Dev. 14, 1132–1145 (2000).

    CAS  PubMed  Google Scholar 

  8. Migliaccio, E. et al. The p66(shc) adapter protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999).

    Article  CAS  Google Scholar 

  9. Conti, L. et al. Expression and activation of SH2/PTB-containing ShcA adapter protein reflects the pattern of neurogenesis in the mammalian brain. Proc. Natl. Acad. Sci. USA 94, 8185–8190 (1997).

    Article  CAS  Google Scholar 

  10. O'Bryan, J. P., Songyang, Z., Cantley, L., Der, C. J. & Pawson, T. A mammalian adapter protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain. Proc. Natl. Acad. Sci. USA 93, 2729–2734 (1996).

    Article  CAS  Google Scholar 

  11. Pelicci, G. et al. A family of Shc related proteins with conserved PTB, CH1 and SH2 regions. Oncogene 13, 633–641 (1996).

    CAS  PubMed  Google Scholar 

  12. Nakamura, T. et al. N-Shc and Sck, two neuronally expressed Shc adapter homologs. J. Biol. Chem. 273, 6960–6967 (1998).

    Article  CAS  Google Scholar 

  13. O'Bryan, J. P., Lamber, Q. T. & Der, C. J. The src homology 2 and phosphotyrosine binding domains of the ShcC adapter protein function as inhibitors of mitogenic signaling by the epidermal growth factor receptor. J. Biol. Chem. 273, 20431–20437 (1998).

    Article  CAS  Google Scholar 

  14. Cattaneo, E. & Conti, L. Characterization of conditionally immortalized striatal derived ST14A cells. J. Neurosci. Res. 53, 223–234 (1998).

    Article  CAS  Google Scholar 

  15. Rigamonti, D. et al. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci. 20, 3705–3713 (2000).

    Article  CAS  Google Scholar 

  16. Cho, K. O., Hunt, C. A. & Kennedy, M. B. The rat brain postsynaptic density fraction contains a homolog of the Drosophila Disc-Large tumor suppressor protein. Neuron 9, 929–942 (1999).

    Article  Google Scholar 

  17. Rozakis-Adcock, M. et al. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 360, 689–692 (1992).

    Article  CAS  Google Scholar 

  18. Yao, R. & Cooper, G. M. Requirement for phosphatidylinosotol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267, 2003–2006 (1995).

    Article  CAS  Google Scholar 

  19. Franke, T. F. et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81,727–736 (1995).

    Article  CAS  Google Scholar 

  20. Marte, B. M. & Downward, J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem. 22, 355–358 (1997).

    Article  CAS  Google Scholar 

  21. Hemmings, B. A. Akt signalling: linking membrane events to life and death decisions. Science 275, 628–630 (1997).

    Article  CAS  Google Scholar 

  22. Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).

    Article  CAS  Google Scholar 

  23. Yang, E. et al. Bad, a heterodimeric partner for Bcl-Xl and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285–291 (1995).

    Article  CAS  Google Scholar 

  24. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).

    CAS  PubMed  Google Scholar 

  25. Johe, K. K., Hazel, T. G., Muller, T., Dugich-Djordjevic, M. M. & McKay, R. D. G. Single factors direct the differentiation of stem-like cells from foetal and adult nervous system. Genes Dev. 10, 3129–3140 (1996).

    Article  CAS  Google Scholar 

  26. Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus substained extracellular signal-regulated kinase activation. Cell 80,179–185 (1995).

    Article  CAS  Google Scholar 

  27. York, R. D. et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392, 622–626 (1998).

    Article  CAS  Google Scholar 

  28. Zha, J. P. et al. Serine phosphorylation of death agonist Bad in response to survival factor results in binding to 14-3-3 not Bcl-XL . Cell 87, 619–628 (1996).

    Article  CAS  Google Scholar 

  29. Fang, X. J. et al. Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18, 6635–6640 (1999).

    Article  CAS  Google Scholar 

  30. Bonni, A. et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358–1362 (1999).

    Article  CAS  Google Scholar 

  31. Klesse, L. J. et al. Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells. Oncogene 18, 2055–2068 (1999).

    Article  CAS  Google Scholar 

  32. Sakai, R. et al. The mammalian SheB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons. Neuron 28, 819–833 (2000).

    Article  CAS  Google Scholar 

  33. Grignani, F. et al. High-efficiency gene transfer and selection of human hematopoietic progenitor cells with a hybrid EBV/retroviral vector expressing the green fluorescence protein. Cancer Res. 58, 14–19 (1998).

    CAS  PubMed  Google Scholar 

  34. Cattaneo, E., Conti, L., Gritti, A., Govoni, S. & Vescovi, A. Non virally mediated gene transfer into human CNS precursor cells. Mol. Brain Res. 42, 161–166 (1996).

    Article  CAS  Google Scholar 

  35. Brewer, G. J. Serum-free B27/neurobasal medium supports differentiated growth of neurons from the striatum, substantia nigra, septum, cerebral cortex, cerebellum, and dentate gyrus. J. Neurosci. Res. 42, 674–683 (1995).

    Article  CAS  Google Scholar 

  36. Carayon, P. & Bord, A. Identification of DNA-replicating lymphocyte subsets using a new method to label the bromo-deoxyuridine incorporated into the DNA. J. Immunol. Methods 147, 225–230 (1992).

    Article  CAS  Google Scholar 

  37. Bonfanti, L., Peretto, P., Merighi, A. & Fasolo, A. Newly-generated cells from the rostral migratory stream in the accessory olfactory bulb of the adult rat. Neuroscience 81, 489–502 (1997).

    Article  CAS  Google Scholar 

  38. Shu, S. Y., Ju, G. & Fan, L. Z. The glucose oxidase-DAB-nickel method in peroxidase histochemistry of the nervous system. Neurosci. Lett. 85, 169–171 (1988).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Associazione Italiana Ricerca Cancro and Ministry of University and Technological Research (Italy #9905261712) to E.C., by Telethon (Italy, E1025) to L.C., and Telethon (Italy, A128) and C.N.R. (P.S. Basi Biologiche Malattie Neurodegenerative) to L.M. We thank R. DeBona and M. De Simone for their help with the cell cultures and immunoreactions, and F. Benvenuto for help with the FACS analysis. We also thank P. Delli Santi for her technical support and L. Chiappino for her photographic expertise.

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Correspondence to Elena Cattaneo.

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Conti, L., Sipione, S., Magrassi, L. et al. Shc signaling in differentiating neural progenitor cells. Nat Neurosci 4, 579–586 (2001). https://doi.org/10.1038/88395

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