Skip to main content

Thank you for visiting 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.

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


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.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


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

    Book  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    ADS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    ADS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Peunova, N., Enikolopov, G. Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells. Nature 375, 68–73 (1995).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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