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Small-molecule activation of neuronal cell fate

Abstract

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.

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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.

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Acknowledgements

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.

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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.

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Correspondence to Jenny Hsieh.

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

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Schneider, J., Gao, Z., Li, S. et al. Small-molecule activation of neuronal cell fate. Nat Chem Biol 4, 408–410 (2008). https://doi.org/10.1038/nchembio.95

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