Epigenetic control of neural stem cell fate

Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Current Opinion in Genetics & Development (Impact Factor: 7.57). 11/2004; 14(5):461-9. DOI: 10.1016/j.gde.2004.07.006
Source: PubMed


Unraveling the mechanisms by which neural stem cells generate distinct cell types remains a central challenge in central nervous system (CNS) biology. Recent studies have shown that epigenetic gene regulation plays an important role in the control of cell growth and differentiation. These epigenetic controls cover a wide spectrum, including the interaction of chromatin remodeling enzymes with neurogenic transcription factors, the maintenance of genome stability in neuronal cells and the involvement of noncoding RNAs in neural fate specification. Extracellular signaling systems that control the growth and differentiation of neural stem cells act, at least in part, by interfacing with these diverse epigenetic mechanisms.

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    • "There is increasing understanding of the secreted external and internal signals necessary for glial cells to develop, including leukemia inhibitory factor (LIF), bone morphogenetic proteins (BMPs), sonic hedgehog (SHH) and their intracellular signaling pathways [7,10-12]. There is also evidence that epigenetic factors cooperate with signaling in these three pathways [13,14]. However, little is known about the role that specific epigenetic factors play in the development of optic nerve glia. "
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    ABSTRACT: Background Histone deacetylases (HDACs) play important roles in glial cell development and in disease states within multiple regions of the central nervous system. However, little is known about HDAC expression or function within the optic nerve. As a first step in understanding the role of HDACs in optic nerve, this study examines the spatio-temporal expression patterns of methylated histone 3 (K9), acetylated histone 3 (K18), and HDACs 1–6 and 8–11 in the developing murine optic nerve head. Results Using RT-qPCR, western blot and immunofluorescence, three stages were analyzed: embryonic day 16 (E16), when astrocyte precursors are found in the optic stalk, postnatal day 5 (P5), when immature astrocytes and oligodendrocytes are found throughout the optic nerve, and P30, when optic nerve astrocytes and oligodendrocytes are mature. Acetylated and methylated histone H3 immunoreactivity was co-localized in the nuclei of most SOX2 positive glia within the optic nerve head and adjacent optic nerve at all developmental stages. HDACs 1–11 were expressed in the optic nerve glial cells at all three stages of optic nerve development in the mouse, but showed temporal differences in overall levels and subcellular localization. HDACs 1 and 2 were predominantly nuclear throughout optic nerve development and glial cell maturation. HDACs 3, 5, 6, 8, and 11 were predominantly cytoplasmic, but showed nuclear localization in at least one stage of optic nerve development. HDACs 4, 9 and10 were predominantly cytoplasmic, with little to no nuclear expression at any time during the developmental stages examined. Conclusions Our results showing that HDACs 1, 2, 3, 5, 6, 8, and 11 were each localized to the nuclei of SOX2 positive glia at some stages of optic nerve development and maturation and extend previous reports of HDAC expression in the aging optic nerve. These HDACs are candidates for further research to understand how chromatin remodeling through acetylation, deacetylation and methylation contributes to glial development as well as their injury response.
    Full-text · Article · Jul 2014 · BMC Developmental Biology
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    • "Interestingly, it is also now apparent that these molecular mechanisms interact and converge upon chromatin to exert transcriptional control and thus together may contribute to the epigenetic basis of cellular identity. The chromatin-based regulation of NSCs and their daughter cell lineages is a growing area of scientific investigation (Hsieh and Gage, 2004; Hirabayashi and Gotoh, 2010; Lee and Lee, 2010), and research into this aspect of the epigenetic landscape promises to reveal new, fundamental principles of neural development. "
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    ABSTRACT: In specific regions of the adult mammalian brain, neural stem cells (NSCs) generate new neurons throughout life. Emerging evidence indicate that chromatin-based transcriptional regulation is a key epigenetic mechanism for the life-long function of adult NSCs. In the adult mouse brain, NSCs in the subventricular zone (SVZ) retain the ability to produce both neurons and glia for the life of the animal. In this review, we discuss the origin and function of SVZ NSCs as they relate to key epigenetic concepts of development and potential underlying mechanism of chromatin-based transcriptional regulation. A central point of discussion is how SVZ NSCs - which possess many characteristics of mature, non-neurogenic astrocytes - maintain a "youthful" ability to produce both neuronal and glial lineages. In addition to reviewing data regarding the function of chromatin-modifying factors in SVZ neurogenesis, we incorporate our growing understanding that long non-coding RNAs serve as an important element to chromatin-based transcriptional regulation, including that of SVZ NSCs. Discoveries regarding the epigenetic mechanisms of adult SVZ NSCs may provide key insights into fundamental principles of adult stem cell biology as well as the more complex and dynamic developmental environment of the embryonic brain.
    Full-text · Article · Oct 2013 · Frontiers in Genetics
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    • "Indeed, NPCs can be isolated from the adult brain and expanded under the stimulation of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) in adherent or in suspension (neurosphere) cultures with high efficacy (Babu et al., 2011; Reynolds et al., 1992; Steffenhagen et al., 2011; Wachs et al., 2003). In vitro, the differentiation of NPCs into neurons typically requires growth-factor removal and the addition of active molecules such as retinoic acid or valproic acid or of neurotrophic factors such as brainderived neurotrophic factor (BDNF) (Hsieh and Gage, 2004; Takahashi et al., 1999). "
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    ABSTRACT: The differentiation of adult neural progenitors (NPCs) into functional neurons is still a limiting factor in the neural stem cell field but mandatory for the potential use of NPCs in therapeutic approaches. Neuronal function requires the appropriate electrophysiological properties. Here, we demonstrate that priming of NPCs using transforming growth factor (TGF)-β1 under conditions that usually favor NPCs' proliferation induces electrophysiological neuronal properties in adult NPCs. Gene chip array analyses revealed upregulation of voltage-dependent ion channel subunits (Kcnd3, Scn1b, Cacng4, and Accn1), neurotransmitters, and synaptic proteins (Cadps, Snap25, Grik4, Gria3, Syngr3, and Gria4) as well as other neuronal proteins (doublecortin [DCX], Nrxn1, Sept8, and Als2cr3). Patch-clamp analysis demonstrated that control-treated cells expressed only voltage-dependent K+-channels of the delayed-rectifier type and the A-type channels. TGF-β1-treated cells possessed more negative resting potentials than nontreated cells owing to the presence of delayed-rectifier and inward-rectifier channels. Furthermore, TGF-β1-treated cells expressed voltage-dependent, TTX-sensitive Na+ channels, which showed increasing current density with TGF-β1 treatment duration and voltage-dependent (+)BayK8644-sensitive L-Type Ca2+ channels. In contrast to nontreated cells, TGF-β1-treated cells responded to current injections with action-potentials in the current-clamp mode. Furthermore, TGF-β1-treated cells responded to application of GABA with an increase in membrane conductance and showed spontaneous synaptic currents that were blocked by the GABA-receptor antagonist picrotoxine. Only NPCs, which were treated with TGF-β1, showed Na+ channel currents, action potentials, and GABAergic currents. In summary, stimulation of NPCs by TGF-β1 fosters a functional neuronal phenotype, which will be of relevance for future cell replacement strategies in neurodegenerative diseases or acute CNS lesions.
    Full-text · Article · Aug 2013 · Glia
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