Activation of Postnatal Neural Stem Cells Requires Nuclear Receptor TLX

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2011; 31(39):13816-28. DOI: 10.1523/JNEUROSCI.1038-11.2011
Source: PubMed


Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The molecular mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphology for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq analysis of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner, and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.

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Available from: Chun-Li Zhang, Oct 06, 2015
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    • "Transcription factors controlling stem-cell maintenance and proliferation are connected via cross-regulatory loops. Notch signaling through RBPJk, for example, controls Sox2 expression ; TLX expression is regulated by Sox2 (Shimozaki et al. 2011); activity of the PI3K pathway is modulated by TLX (Zhang et al. 2006; Niu et al. 2011), whereas the PI3K-regu- lated transcription factor FoxO3 controls expression of Notch pathway components (Webb et al. 2013). The involvement of cross-regulatory loops to control specific developmental stages may provide the advantage of a self-regulatory transcriptional network, which on one hand is largely self-sufficient and robust, but on the other hand, can be quickly dissolved by dysregulation of a single factor to induce lineage progression (Fig. 2). "
    Cold Spring Harbor perspectives in biology 10/2015; 7(10):a018879. DOI:10.1101/cshperspect.a018879 · 8.68 Impact Factor
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    • "Stem cells are present in two regions of the postnatal and adult brain: the subependymal zone (SEZ) adjacent to the lateral ventricles and the dentate gyrus (DG) of the hippocampus, where they continuously generate new neurons that integrate into neuronal circuits of the olfactory bulb and hippocampus, respectively (Temple 2001; Fuentealba et al. 2012). In contrast to the highly proliferative stem cells of the embryonic neural tube, NSCs in the postnatal and adult brain are relatively quiescent (Temple 2001; Niu et al. 2011; Fuentealba et al. 2012). Adult NSCs are stimulated to divide by diverse physiological stimuli, including physical exercise and cognitive stimulation, while conversely, stress, anxiety, and old age suppress their divisions (Fabel and Kempermann 2008; Ma et al. 2009; Lucassen et al. 2010). "
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    • "It is expressed by a small subset of RGLs, identified by their radial morphology and expression of GFAP. Most Ascl1-positive RGLs are activated, as 83.3% ± 16.7% of them express the cell cycle and cell activation marker MCM2 (Machida et al., 2005; Niu et al., 2011) (Figures 1B and 1C). "
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    ABSTRACT: The activity of adult stem cells is regulated by signals emanating from the surrounding tissue. Many niche signals have been identified, but it is unclear how they influence the choice of stem cells to remain quiescent or divide. Here we show that when stem cells of the adult hippocampus receive activating signals, they first induce the expression of the transcription factor Ascl1 and only subsequently exit quiescence. Moreover, lowering Ascl1 expression reduces the proliferation rate of hippocampal stem cells, and inactivating Ascl1 blocks quiescence exit completely, rendering them unresponsive to activating stimuli. Ascl1 promotes the proliferation of hippocampal stem cells by directly regulating the expression of cell-cycle regulatory genes. Ascl1 is similarly required for stem cell activation in the adult subventricular zone. Our results support a model whereby Ascl1 integrates inputs from both stimulatory and inhibitory signals and converts them into a transcriptional program activating adult neural stem cells.
    Neuron 09/2014; 83(5):1085–1097. DOI:10.1016/j.neuron.2014.08.004 · 15.05 Impact Factor
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