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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    • "Even though no obvious defects are found in the brains of Tlx null mice during early development , mature mice exhibit limbic defects, retinopathies, reduced copulation, and progressively violent behavior (Islam and Zhang, 2015; Monaghan et al., 1997; Yu et al., 2000). The primary function of this key transcriptional regulator is to prevent the precocious differentiation of NSCs in the developing and adult brain (Li et al., 2008; Niu et al., 2011; Roy et al., 2004; Shi et al., 2004). TLX controls the expression of a broad network of genes to maintain NSC pools in an undifferentiated, self-renewing state (Niu et al., 2011; Shi et al., 2004, 2008; Zhang et al., 2008). "
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    ABSTRACT: The orphan nuclear receptor TLX is a master regulator of postnatal neural stem cell (NSC) self-renewal and neurogenesis; however, it remains unclear how TLX expression is precisely regulated in these tissue-specific stem cells. Here, we show that a highly conserved cis-element within the Tlx locus functions to drive gene expression in NSCs. We demonstrate that the transcription factors SOX2 and MYT1 specifically interact with this genomic element to directly regulate Tlx enhancer activity in vivo. Knockdown experiments further reveal that SOX2 dominantly controls endogenous expression of TLX, whereas MYT1 only plays a modulatory role. Importantly, TLX is essential for SOX2-mediated in vivo reprogramming of astrocytes and itself is also sufficient to induce neurogenesis in the adult striatum. Together, these findings unveil functional genetic interactions among transcription factors that are critical to NSCs and in vivo cell reprogramming.
    Stem Cell Reports 10/2015; DOI:10.1016/j.stemcr.2015.09.015 · 5.37 Impact Factor
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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). "
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    ABSTRACT: Adult-generated dentate granule neurons have emerged as major contributors to hippocampal plasticity. Newneurons are generated fromneural stem cells through a complex sequence of proliferation, differentiation, and maturation steps. Development of the new neuron is dependent on the precise temporal activity of transcription factors, which coordinate the expression of stage-specific genetic programs. Here, we review current knowledge in transcription factor-mediated regulation of mammalian neural stem cells and neurogenesis and will discuss potential mechanisms of how transcription factor networks, on one hand, allow for precise execution of the developmental sequence and, on the other hand, allow for adaptation of the rate and timing of adult neurogenesis in response to complex stimuli. Understanding transcription factor-mediated control of neuronal development will provide new insights into the mechanisms underlying neurogenesis-dependent plasticity in health and disease. © 2015 Cold Spring Harbor Laboratory Press. All rights reserved.
    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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