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.

Small-molecule activation of neuronal cell fate


We probed an epigenetic regulatory path from small molecule to neuronal gene activation. Isoxazole small molecules triggered robust neuronal differentiation in adult neural stem cells, rapidly signaling to the neuronal genome via Ca2+ influx. Ca2+-activated CaMK phosphorylated and mediated nuclear export of the MEF2 regulator HDAC5, thereby de-repressing neuronal genes. These results provide new tools to explore the epigenetic signaling circuitry specifying neuronal cell fate and new leads for neuro-regenerative drugs.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Isoxazoles trigger neuronal differentiation through a neurotransmitter-evoked Ca2+ signal.
Figure 2: Isoxazole signaling leads to activation of CaMK, phosphorylation/export of HDAC5 and MEF2-dependent gene expression in NSCs.


  1. Diamandis, P. et al. Nat. Chem. Biol. 3, 268–273 (2007).

    CAS  Article  Google Scholar 

  2. Deisseroth, K. et al. Neuron 42, 535–552 (2004).

    CAS  Article  Google Scholar 

  3. Tozuka, Y., Fukuda, S., Namba, T., Seki, T. & Hisatsune, T. Neuron 47, 803–815 (2005).

    CAS  Article  Google Scholar 

  4. Lyons, G.E., Micales, B.K., Schwarz, J., Martin, J.F. & Olson, E.N. J. Neurosci. 15, 5727–5738 (1995).

    CAS  Article  Google Scholar 

  5. Sadek, H. et al. Proc. Natl. Acad. Sci. USA 105, 6063–6068 (2008).

    CAS  Article  Google Scholar 

  6. Skerjanc, I.S. & Wilton, S. FEBS Lett. 472, 53–56 (2000).

    CAS  Article  Google Scholar 

  7. Riazi, A.M., Lee, H., Hsu, C. & Van Arsdell, G. J. Biol. Chem. 280, 10716–10720 (2005).

    CAS  Article  Google Scholar 

  8. Gage, F.H. et al. Proc. Natl. Acad. Sci. USA 92, 11879–11883 (1995).

    CAS  Article  Google Scholar 

  9. Mao, Z., Bonni, A., Xia, F., Nadal-Vicens, M. & Greenberg, M.E. Science 286, 785–790 (1999).

    CAS  Article  Google Scholar 

  10. Krainc, D. et al. J. Biol. Chem. 273, 26218–26224 (1998).

    CAS  Article  Google Scholar 

  11. McKinsey, T.A., Zhang, C.L. & Olson, E.N. Trends Biochem. Sci. 27, 40–47 (2002).

    CAS  Article  Google Scholar 

  12. Grozinger, C.M. & Schreiber, S.L. Proc. Natl. Acad. Sci. USA 97, 7835–7840 (2000).

    CAS  Article  Google Scholar 

  13. Chawla, S., Vanhoutte, P., Arnold, F.J., Huang, C.L. & Bading, H. J. Neurochem. 85, 151–159 (2003).

    CAS  Article  Google Scholar 

  14. McKinsey, T.A., Zhang, C.L., Lu, J. & Olson, E.N. Nature 408, 106–111 (2000).

    CAS  Article  Google Scholar 

  15. Vega, R.B. et al. Mol. Cell. Biol. 24, 8374–8385 (2004).

    CAS  Article  Google Scholar 

Download references


We thank L. Zhang, B. Hannack, T. Hsu and K. Ure for technical assistance. We thank T. McKinsey (Gilead Colorado, Inc.) for the phosphorylated HDAC5 antibody, G. Bai (University of Maryland) for the NR1-luciferase construct, S. Goetsch for technical assistance and artwork, and A. Barbosa (University of Texas Southwestern), J. Backs (University of Texas Southwestern) and E. Olson (University of Texas Southwestern) for sharing reagents and helpful critique of the manuscript. We also thank F. Gage, S. McKnight, O. Cleaver and A. Chang for helpful comments on the manuscript. Work was funded in part by grants from the Reynolds Foundation (J.W.S.), the US National Institutes of Health, National Institute of Neurological Disorders and Stroke (R01NS38082; I.B.), the Ellison Medical Foundation (AG-NS-0371-06; J.H.) and the Welch Foundation (I-1660; J.H.). J.H. is the recipient of a fellowship from the Esther A. and Joseph Klingenstein Fund and of the University of Texas Southwestern President's Research Council Young Researcher Award.

Author information

Authors and Affiliations



J.W.S., I.B., D.E.F. and J.H. designed experiments. J.W.S., Z.G., S.L., M.F., T.-S.T., D.E.F. and J.H. performed experiments. J.W.S. and J.H. wrote the paper.

Corresponding author

Correspondence to Jenny Hsieh.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Discussion and Supplementary Methods (PDF 2565 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schneider, J., Gao, Z., Li, S. et al. Small-molecule activation of neuronal cell fate. Nat Chem Biol 4, 408–410 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


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