The Neural Stem Cell Fate Determinant TLX Promotes Tumorigenesis and Genesis of Cells Resembling Glioma Stem Cells

Park, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min; Oh, Sang-Ho; Kim, Sung-Hak; Nam, Do‐Hyun; Kim, Hyunggee

doi:10.1007/s10059-010-0122-z

Cited by 44 publications

(41 citation statements)

References 27 publications

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“…Overexpression of TLX in NSCs or glial cells is sufficient to sensitize them to tumorigenesis under either a p53 Ϫ/Ϫ or Ink4a/ Arf Ϫ/Ϫ genetic background (18,28). This implicates TLX as a potential therapeutic target against gliomas (18).…”

Section: Discussionmentioning

confidence: 99%

“…1 and 7), lending to its use as a diagnostic biomarker (18,28,30,34,42). Future experiments are warranted to tease out the signaling path- .…”

Section: Discussionmentioning

confidence: 99%

“…As a key regulator of NSC proliferation, it is not surprising that TLX has been implicated in gliomagenesis. When combined with inactivation of p53 or Ink4a/Arf, ectopic expression of TLX is sufficient for glioma formation in a mouse model (18,28). However, whether TLX is required for gliomagenesis or tumor maintenance is not known.…”

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confidence: 99%

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

Zou

Niu²,

Qin

et al. 2012

Molecular and Cellular Biology

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bNeural 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. The subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle (LV) are the two neurogenic niches in the adult brain where neural stem cells (NSCs) reside and continually produce functional neurons (12,24,39). The orphan nuclear receptor TLX (also known as NR2E1) regulates proliferation in these NSCs by modulating the expression of Pten, p21, and several other genes downstream of p53 (17,18,26,32,46). However, the genetic interactions between TLX and these genes have not been examined.The characteristic self-renewal of NSCs renders them prone to mutation, deregulated proliferation, and differentiation, all hallmarks of neoplasms in the central nervous system (CNS). Indeed, emerging evidence indicates that NSCs are the cellular origin of gliomas (1, 43, 48). Mutagenesis through viral or chemical carcinogens preferentially induces brain tumors in the vicinity of the neurogenic niche (4,5,14,27). These results were further corroborated with the recent development of mouse models that are induced by mutation of the tumor suppressor p53, Pten, Nf1, Rb, or Ink4a/Arf or activation of the oncogene Ras, Akt, or Egfr (1,11,21,43,48,49). As a key regulator of NSC proliferation, it is not surprising that TLX has been implicated in gliomagenesis. When combined with inactivation of p53 or Ink4a/Arf, ectopic expression of TLX is sufficient for glioma formation in a mouse model (18, 28). However, whether TLX is required for gliomagenesis or tumor maintenance is not known. Furthermore, the relationship between gliomagenesis and normal adult neurogenesis requires additional investigation. Here, we examined the role of TLX and TLX-dependent NSCs in a mouse model of gliomagenesis. MATERIALS AND METHODSAnimals. Strategies and methods for generating the following mutant mice have been described:, and hGfap-Cre (50) mice. All mice were...

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Section: Discussionmentioning

confidence: 99%

“…1 and 7), lending to its use as a diagnostic biomarker (18,28,30,34,42). Future experiments are warranted to tease out the signaling path- .…”

Section: Discussionmentioning

confidence: 99%

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

Zou

Niu²,

Qin

et al. 2012

Molecular and Cellular Biology

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“…On the contrary, elevated expression of TLX has been reported in various types of human glioma [68][69][70][71][72][73] and glioma cell lines [74], and TLX overexpression seems to be associated with a poor prognosis for patients with glioma [74]. A recent study further reported that TLX promotes the progression of neuroblastoma and is correlated with poor survival [56].…”

Section: Tlx and Human Diseasesmentioning

confidence: 99%

The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases

Wang

Xiong

2016

Neurosci. Bull.

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The human TLX gene encodes an orphan nuclear receptor predominantly expressed in the central nervous system. Tailess and Tlx, the TLX homologues in Drosophila and mouse, play essential roles in body-pattern formation and neurogenesis during early embryogenesis and perform crucial functions in maintaining stemness and controlling the differentiation of adult neural stem cells in the central nervous system, especially the visual system. Multiple target genes and signaling pathways are regulated by TLX and its homologues in specific tissues during various developmental stages. This review aims to summarize previous studies including many recent updates from different aspects concerning TLX and its homologues in Drosophila and mouse.

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“…TLX also promotes neural stem cell self-renewal by down-regulating the expression of cell cycle check genes such as PTEN and p21 (Zhang et al 2006;Sun et al 2007). Elevated expression of TLX has also been implicated in gliomagenesis, making it a promising therapeutic target for the treatment of human brain tumors (Liu et al 2010;Park et al 2010;Zou et al 2012;Xie et al 2014). A number of corepressors of TLX have been identified, which include Atrophin proteins, LSD1 (lysine-specific demethylase), and histone deacetylases (HDACs) (Wang et al 2006;Sun et al 2007Sun et al , 2010Yokoyama et al 2008), among which Atrophin proteins are directly recruited by TLX.…”

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confidence: 99%

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Zhi

Zhou

et al. 2015

Genes Dev.

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The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX-Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.

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The Neural Stem Cell Fate Determinant TLX Promotes Tumorigenesis and Genesis of Cells Resembling Glioma Stem Cells

Cited by 44 publications

References 27 publications

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

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

The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

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