The Nuclear Receptor TLX Is Required for Gliomagenesis within the Adult Neurogenic Niche

Department of Molecular Biology.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2012; 32(23). DOI: 10.1128/MCB.01122-12
Source: PubMed


Neural stem cells (NSCs) continually generate functional neurons in the adult brain. Due to their ability to proliferate,
deregulated NSCs or their progenitors have been proposed as the cells of origin for a number of primary central nervous system
neoplasms, including infiltrating gliomas. The orphan nuclear receptor TLX is required for proliferation of adult NSCs, and
its upregulation promotes brain tumor formation. However, it is unknown whether TLX is required for gliomagenesis. We examined
the genetic interactions between TLX and several tumor suppressors, as well as the role of TLX-dependent NSCs during gliomagenesis,
using mouse models. Here, we show that TLX is essential for the proliferation of adult NSCs with a single deletion of p21, p53, or Pten or combined deletion of Pten and p53. While brain tumors still form in Tlx mutant mice, these tumors are less infiltrative and rarely associate with the adult neurogenic niches, suggesting a non-stem-cell
origin. Taken together, these results indicate a critical role for TLX in NSC-dependent gliomagenesis and implicate TLX as
a therapeutic target to inhibit the development of NSC-derived brain tumors.

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    • "TLX-dependent adult neurogenesis has a critical role in normal spatial learning and memory (Zhang et al., 2008). TLX-regulated proliferation of NSCs is also required for gliomagenesis in the adult neurogenic niches (Zou et al., 2012). TLX controls NSC quiescence and positioning in the neurogenic niche by modulating gene expression in multiple pathways including p53-p21 (Niu et al., 2011). "
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    ABSTRACT: Neural stem cells (NSCs) are self-renewing multipotent progenitors that generate both neurons and glia. The precise control of NSC behavior is fundamental to the architecture and function of the central nervous system. We previously demonstrated that the orphan nuclear receptor TLX is required for postnatal NSC activation and neurogenesis in the neurogenic niche. Here, we show that TLX modulates bone morphogenetic protein (BMP)-SMAD signaling to control the timing of postnatal astrogenesis. Genes involved in the BMP signaling pathway, such as Bmp4, Hes1, and Id3, are upregulated in postnatal brains lacking Tlx. Chromatin immunoprecipitation and electrophoretic mobility shift assays reveal that TLX can directly bind the enhancer region of Bmp4. In accordance with elevated BMP signaling, the downstream effectors SMAD1/5/8 are activated by phosphorylation in Tlx mutant mice. Consequently, Tlx mutant brains exhibit an early appearance and increased number of astrocytes with marker expression of glial fibrillary acidic protein (GFAP) and S100B. Taken together, these results suggest that TLX tightly controls postnatal astrogenesis through the modulation of BMP-SMAD signaling pathway activity.
    Frontiers in Neuroscience 04/2014; 8:74. DOI:10.3389/fnins.2014.00074 · 3.66 Impact Factor
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    • "Overexpression of TLX increases cell division in the SVZ, and also stimulates angiogenesis (Liu et al., 2010). Tumor suppressive pathways are also major regulators of adult neurogenesis (Zhao et al., 2008; Hsieh, 2012; Zou et al., 2012; Bartesaghi and Salomoni, 2013). PTEN is an important tumor suppressor gene regulating neuronal differentiation (Lachyankar et al., 2000), precursor migration (Li et al., 2003) and also tumor initiation and maintenance (Hongwu et al., 2008). "
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    ABSTRACT: Adult neurogenesis in mammals is predominantly restricted to two brain regions, the dentate gyrus of the hippocampus and the olfactory bulb, suggesting that these two brain regions uniquely share functions that mediate its adaptive significance. Benefits of adult neurogenesis across these two regions appear to converge on increased neuronal and structural plasticity that subserves coding of novel, complex, and fine-grained information, usually with contextual components that include spatial positioning. By contrast, costs of adult neurogenesis appear to center on potential for dysregulation resulting in higher risk of brain cancer or psychological dysfunctions, but such costs have yet to be quantified directly. The three main hypotheses for the proximate functions and adaptive significance of adult neurogenesis, pattern separation, memory consolidation, and olfactory spatial, are not mutually exclusive and can be reconciled into a simple general model amenable to targeted experimental and comparative tests. Comparative analysis of brain region sizes across two major social-ecological groups of primates, gregarious (mainly diurnal haplorhines, visually-oriented, and in large social groups) and solitary (mainly noctural, territorial, and highly reliant on olfaction, as in most rodents) suggest that solitary species, but not gregarious species, show positive associations of population densities and home range sizes with sizes of both the hippocampus and olfactory bulb, implicating their functions in social-territorial systems mediated by olfactory cues. Integrated analyses of the adaptive significance of adult neurogenesis will benefit from experimental studies motivated and structured by ecologically and socially valid selective contexts.
    Frontiers in Neuroanatomy 07/2013; 7(21). DOI:10.3389/fnana.2013.00021 · 3.54 Impact Factor
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    ABSTRACT: Living organisms require a host of regulatory circuits in order to survive optimally in a given environment. Gene regulation is one of the most important mechanisms for achieving normal cellular activities and overall homeostasis. The orphan nuclear receptors (ONRs) belonging to the nuclear receptors (NR) superfamily are mediators of pleiotropic effects in multiple cell types via control of gene expression. A huge volume of studies, especially in the past two decades, has revealed the detailed structures and many functions of the ONRs. However, many biological functions governed by the ONRs through gene control remain elusive. Moreover, gene regulatory mechanisms of the ONRs are still being dissected. The ONRs can interact with other members of the NR superfamily, forming heteromeric complexes at the DNA binding sites to modulate gene transcription. Additionally, the ONRs’ gene regulatory abilities are further controlled via interactions with a host of coregulators. Data from several studies have unequivocally shown that the ONRs are unique regulators of biological processes, including energy and general metabolism, immunity, growth and reproduction, cell proliferation and specialization, sensory control, and many others. Furthermore, the evidence has suggested the modulatory role played by the ONRs in the onset and progression of diseases and that targeting their activities might provide a vital tool in the treatment of various diseases. Here, the current perspective on the ONRs is being reviewed. Keywords: orphan nuclear receptors, gene regulation, gene expression, coregulators
    Journal of Receptor, Ligand and Channel Research 11/2013; DOI:10.2147/JRLCR.S52252
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