Small-molecule activation of neuronal cell fate

Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Nature Chemical Biology (Impact Factor: 13.22). 08/2008; 4(7):408-10. DOI: 10.1038/nchembio.95
Source: PubMed

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 Ca(2+) influx. Ca(2+)-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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Available from: Ilya Bezprozvanny, Sep 03, 2015
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    • "Also in vitro, proliferation of rat cerebellar granule cell precursors is modulated by Ca 21 dynamics (Borodinsky and Fiszman, 1998) triggered by depolarizing GABA signaling (Fiszman et al., 1999). Moreover, an in vitro screening of isoxazole small molecules that trigger robust neuronal differentiation of adult neural stem cells indicates that these drugs elicit glutamate-and Ca 21 -mediated signaling that recruits MEF2 by derepressing the inhibitory action exerted by histone deacetylase 5 (Schneider et al., 2008). Interestingly, membrane depolarization regulates splicing of the neural cell adhesion molecule (NCAM) by causing H3K9 hyper-acetylation in a specific internal region of the ncam gene (Schor et al., 2009) and localization of different NCAM splice variants is associated with different states of neuronal differentiation and function (Pollerberg et al., 1985; Polo-Parada et al., 2004). "
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    • "). In the CNS, Class IIa HDACs controls neuronal survival (Linseman et al. 2003; Bolger and Yao 2005; Chen and Cepko 2009), differentiation (Schneider et al. 2008), long-term-memory-related synaptic plasticity (Guan et al. 2002), and behavioral responses (Tsankova et al. 2006; Renthal et al. 2007; Taniguchi et al. 2012). A characteristic of Class IIa HDACs is that their ability to suppress transcription in the nucleus is subject to dynamic regulation. "
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    • "When the b-isox chemical was applied to lysates prepared from a variety of cell or tissue types, it triggered the precipitation of a select group of proteins associated with RNA biogenesis (Figure 1). This unusual property of the b-isox compound is unlikely to have anything to do with the ability of the parental isoxazole to cause mouse embryonic stem cells to differentiate into cardiac myocytes (Sadek et al., 2008) or to cause neuronal stem cells to adopt the morphology of differentiated neurons (Schneider et al., 2008). This conclusion is based upon the observation that the parental isoxazole has no capacity whatsoever to cause precipitation of the spectrum of RNA-binding proteins described in this study (data not shown). "
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