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Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells

Abstract

ARREST of cell division is a prerequisite for cells to enter a program of terminal differentiation. Mitogenesis and cytostasis of neuronal cell precursors can be induced by the same or by different growth or trophic factors1á€-9. Response of PC12 cells to nerve growth factor (NGF) involves a proliferative phase that is followed by growth arrest and differentiation. Here we present evidence that the cytostatic effect of NGF is mediated by nitric oxide (NO), a second messenger molecule with both para- and autocrine properties that can diffuse freely and act within a restricted volume10á€-14. We show that NGF induces different forms of nitric oxide synthase (NOS) in neuronal cells, that nitric oxide (NO) acts as a cytostatic agent in these cells, that inhibition of NOS leads to reversal of NGF-induced cytostasis and thereby prevents full differentiation, and that capacity of a mutant cell line to differentiate can be rescued by exogenous NO. We suggest that induction of NOS is an important step in the commitment of neuronal precursors and that NOS serves as a growth arrest gene, initiating the switch to cytostasis during differentiation.

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References

  1. Jackobson, M. in Developmental Neurobiology (Plenum, New York, 1991).

    Book  Google Scholar 

  2. McKay, R. D. G. Cell 58, 815–821 (1989).

    Article  CAS  Google Scholar 

  3. Anderson, D. J. A. Rev. Neurosci. 16, 129–158 (1993).

    Article  CAS  Google Scholar 

  4. Green, L. A. & Tishler, A. S. Proc. natn. Acad. Sci. U.S.A. 73, 2424–2428 (1976).

    Article  ADS  Google Scholar 

  5. Burstein, D. E. & Greene, L. Devl. Biol. 94, 477–482 (1982).

    Article  CAS  Google Scholar 

  6. Lilien, L. E. & Claude, P. Nature 317, 632–634 (1985).

    Article  ADS  Google Scholar 

  7. Rudkin, B. P. et al. EMBO J. 8, 3319–3325 (1989).

    Article  CAS  Google Scholar 

  8. McKay, R. D. G. et al. Cold Spring Harb. Symp. quant. Biol. 55, 291–301 (1990).

    Article  CAS  Google Scholar 

  9. Drago, J. et al. Proc. natn. Acad. Sci. U.S.A. 88, 2199–2203 (1991).

    Article  ADS  CAS  Google Scholar 

  10. Garthwaite, J. Trends Neurosci. 14, 60–67 (1991).

    Article  CAS  Google Scholar 

  11. Moncada, S., Palmer, R. M. J. & Higgs, E. A. Pharmac. Rev. 43, 109–142 (1991).

    CAS  Google Scholar 

  12. Bredt, D. S. & Snyder, S. H. Neuron 8, 3–11 (1992).

    Article  CAS  Google Scholar 

  13. Nathan, C. FASEB J. 6, 3051–3064 (1992).

    Article  CAS  Google Scholar 

  14. Bredt, D. S. & Snyder, S. H. A. Rev. Biochem. 63, 175–195 (1994).

    Article  CAS  Google Scholar 

  15. Xie, Q. et al. Science 256, 225–227 (1992).

    Article  ADS  CAS  Google Scholar 

  16. Geller, D. A. et al. Proc. natn. Acad. Sci. U.S.A. 90, 3491–3494 (1993).

    Article  ADS  CAS  Google Scholar 

  17. Nunokawa, Y., Ishuda, N. & Tanaka, S. Biochem. biophys. Res. Commun. 191, 89–94 (1993).

    Article  CAS  Google Scholar 

  18. Wood, E. R. & Berger, H. Biochem. biophys. Res. Commun. 191, 767–774 (1993).

    Article  CAS  Google Scholar 

  19. Garg, U. C. & Hassid, A. J. clin. Invest. 83, 1774–1777 (1989).

    Article  CAS  Google Scholar 

  20. Lepoivre, M. et al. Biochem. biophys. Res. Commun. 179, 442–448 (1991).

    Article  CAS  Google Scholar 

  21. Kwon, N. S., Stuehr, D. J. & Nathan, C. F. J. exp. Med. 174, 761–767 (1991).

    Article  CAS  Google Scholar 

  22. Hogan, M., Cerami, A. & Bucala, R. J. clin. Invest. 90, 1110–1115 (1992).

    Article  CAS  Google Scholar 

  23. Buchkovich, K. J. & Ziff, E. B. Molec. biol. Cell 5, 1225–1241 (1994).

    Article  CAS  Google Scholar 

  24. Peunova, N. & Enikolopov, G. Nature 364, 450–453 (1993).

    Article  ADS  CAS  Google Scholar 

  25. Dawson, T. M. et al. Proc. natn. Acad. Sci. U.S.A. 88, 7797–7801 (1991).

    Article  ADS  CAS  Google Scholar 

  26. Hope, B. T. et al. Proc. natn. Acad. Sci. U.S.A. 88, 2811–2814 (1991).

    Article  ADS  CAS  Google Scholar 

  27. Bredt, D.S. & Snyder, S. H. Proc. natn. Acad. Sci. U.S.A. 87, 682–685 (1990).

    Article  ADS  CAS  Google Scholar 

  28. Hirsch, D. B. et al. Curr. Biol. 3, 749–754 (1993).

    Article  CAS  Google Scholar 

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Peunova, N., Enikolopov, G. Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells. Nature 375, 68–73 (1995). https://doi.org/10.1038/375068a0

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