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). 08/2008; 4(7):408-10. DOI: 10.1038/nchembio.95
Source: PubMed


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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    • "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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    Developmental Neurobiology 04/2015; 75(4). DOI:10.1002/dneu.22254 · 3.37 Impact Factor
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    • "One exciting more recent development in pharmacologically-induced enhancement of endogenous neurogenesis is the implementation of small molecules (Schneider et al. 2008). Through the screening of high-throughput chemical libraries in stem cell-based assays, several small molecules have shown promise to enhance neurogenesis in laboratory animals (Schneider et al. 2008). This relatively new area of research into small molecule modulators of neurogenesis is ripe for exploration as a potential regenerative therapy. "
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    ABSTRACT: With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer's, Huntington's, and Parkinson's diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-of-concept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the "traditional" view of neurodegeneration - overt cell loss - for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult neurogenesis, and a better understanding of the pathological trajectory of each neurodegenerative disease.
    03/2015; 1(3):335-351.
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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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    ABSTRACT: The Class IIa histone deacetylases HDAC4 and HDAC5 play a role in neuronal survival and behavioural adaptation in the CNS. Phosphorylation at 2/3 N-terminal sites promote their nuclear export. We investigated whether non-canonical signaling routes to Class IIa HDAC export exist due to their association with the co-repressor Silencing Mediator Of Retinoic And Thryoid Hormone Receptors (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N-terminal phosphorylation sites (HDAC4(MUT) , HDAC5(MUT) ) are constitutively nuclear, co-expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 (RD3) is critical for co-shuttling of HDAC5(MUT) , consistent with the role for this domain in Class IIa HDAC association. In the context of BDNF signalling, we found that HDAC5(WT) , which was more cytoplasmic than HDAC5(MUT) , accumulated in the nucleus after BDNF treatment. However, co-expression of SMRT blocked BDNF-induced HDAC5(WT) import in a RD3-dependent manner. In effect, SMRT-mediated HDAC5(WT) export was opposing the BDNF-induced HDAC5 nuclear accumulation observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs exportable by a wider range of signals than those which simply promote direct phosphorylation. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12058.
    Journal of Neurochemistry 10/2012; 124(1). DOI:10.1111/jnc.12058 · 4.28 Impact Factor
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