LÄHDE: KR Ravi (2014) Neural Stem Cells, TLX and neuroblastoma.
ISBN 978-91-628-9091-9- Mikä on tämä tumareeptori TLX? Sen synonyymi on NR2E1
- Tietoa vuodelta 2011:
Drosophila Tailless (Tll) ja sen selkärankaisissa esiintyvä homologi TLX.
Se on konservoitunut orpotumaresepotori jota ilmeneee erityisesti silmässä ja etuaivossa.
Tll ja TLX toimivat ensisijaisesti transkription vaimentajina vuorovaikutuksillaan transkription muihin vaimentajiin, Atrofiiniperheen proteiineihin ja histonipäätteitä/kromatiinia muokkaaviin tekijöihin kuten lysiinispesifiseen histonidemetylaasi-1 entsyymiin ja histonideasetylaaseihin(HDAC).
Tll ja Tlx reseptoreiden funktionaalinen tärkeys on oivallettu viime vuosina siitä, että niitä ilmenee neuraalisissa kantasoluissa (NSC) ja solu tarvitsee niitä omaan uudistumiseensa sekä hedelmäkärpäsessä että hiiressä. Otsikon artikkelissa annetaan nopea katsaus Tll ja Tlx reseptoreista, niiden transkriptionaalisesta verkostosta, joka ylläpitää neuraalisia kantasoluja kehityksen aikaisessa ja täysikäisessä eläimessä
LÄHDE: Dev Neurosci. 2011;33(1):1-13. doi: 10.1159/000321585. Epub 2010 Dec 2. A tale of tailless.
Drosophila Tailless(Tll) and its vertebrate homologue Tlx are conserved orphan nuclear receptors specifically expressed in the eye and the forebrain. Tll and Tlx
act primarily as transcriptional repressors through their interactions
with transcriptional corepressors, Atrophin family proteins, and
histone-tail/chromatin-modifying factors such as lysine-specific histone
demethylase 1 and histone deacetylases. The functional importance of
Tll and Tlx is
made apparent by the recent discovery that they are expressed in neural
stem cells (NSCs) and are required for self-renewal of these cells in
both Drosophila and the mouse. This review provides a snapshot of
current knowledge about Tll and Tlx and their transcriptional network, which maintains NSCs in developing and adult animals.
2010 S. Karger AG, Basel.
2010 S. Karger AG, Basel.
- Artikkeleita vuodelta 2014
PubMed hakulaite antaa 68 lähdettä ja katson niistä tuoreimmat. Results: 1 to 20 of 68
1.
Xie Q, Flavahan WA, Bao S, Rich J.
Cell Stem Cell. 2014 Aug 7;15(2):114-6. doi: 10.1016/j.stem.2014.07.004.
Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival. [Cell Stem Cell. 2014]
In this issue of
Cell Stem Cell, Zhu et al. (2014) demonstrate that a genetically
engineered glioma model displays a functional cellular hierarchy defined
by expression of the nuclear orphan receptor Tlx. Targeting cancer stem cells through genetic deletion of TLX promotes cancer stem cell death and differentiation and extends survival.
Comment on
Comment on
2.
Benod
C, Villagomez R, Filgueira CS, Hwang PK, Leonard PG, Poncet-Montange G,
Rajagopalan S, Fletterick RJ, Gustafsson JÅ, Webb P.
PLoS One. 2014 Jun 17;9(6):e99440. doi: 10.1371/journal.pone.0099440. eCollection 2014.
Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chemical probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homology models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helices α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compounds (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compounds could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.
Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chemical probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homology models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helices α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compounds (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compounds could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.
Islam MM, Zhang CL.
Biochim Biophys Acta. 2014 Jun 13. pii: S1874-9399(14)00153-9. doi: 10.1016/j.bbagrm.2014.06.001. [Epub ahead of print] Review.
The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
4.
Murai K, Qu Q, Sun G, Ye P, Li W, Asuelime G, Sun E, Tsai GE, Shi Y.
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9115-20. doi: 10.1073/pnas.1406779111. Epub 2014 Jun 10.
The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.
The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.
5.
Hu Y, Luo M, Ni N, Den Y, Xia J, Chen J, Ji J, Zhou X, Fan X, Gu P.
Stem Cells Dev. 2014 Jul 14. [Epub ahead of print]
Recent research has demonstrated critical roles of a number of microRNAs (miRNAs) in stem cell proliferation and differentiation. miRNA-9 (miR-9) is a brain-enriched miRNA. Whether miR-9 has a role in retinal progenitor cell (RPC) proliferation and differentiation remains unknown. In this study, we show that miR-9 plays an important role in RPC fate determination. The expression of miR-9 was inversely correlated with that of the nuclear receptor TLX, which is an essential regulator of neural stem cell self-renewal. Overexpression of miR-9 downregulated the TLX levels in RPCs, leading to reduced RPC proliferation and increased neuronal and glial differentiation, and the effect of miR-9 overexpression on RPC proliferation and differentiation was inhibited by the TLX overexpression; knockdown of miR-9 resulted in increased TLX expression as well as enhanced proliferation of RPCs. Furthermore, inhibition of endogenous TLX by small interfering RNA suppressed RPC proliferation and promoted RPCs to differentiate into retinal neuronal and glial cells. These results suggest that miR-9 and TLX form a feedback regulatory loop to coordinate the proliferation and differentiation of retinal progenitors.
Recent research has demonstrated critical roles of a number of microRNAs (miRNAs) in stem cell proliferation and differentiation. miRNA-9 (miR-9) is a brain-enriched miRNA. Whether miR-9 has a role in retinal progenitor cell (RPC) proliferation and differentiation remains unknown. In this study, we show that miR-9 plays an important role in RPC fate determination. The expression of miR-9 was inversely correlated with that of the nuclear receptor TLX, which is an essential regulator of neural stem cell self-renewal. Overexpression of miR-9 downregulated the TLX levels in RPCs, leading to reduced RPC proliferation and increased neuronal and glial differentiation, and the effect of miR-9 overexpression on RPC proliferation and differentiation was inhibited by the TLX overexpression; knockdown of miR-9 resulted in increased TLX expression as well as enhanced proliferation of RPCs. Furthermore, inhibition of endogenous TLX by small interfering RNA suppressed RPC proliferation and promoted RPCs to differentiate into retinal neuronal and glial cells. These results suggest that miR-9 and TLX form a feedback regulatory loop to coordinate the proliferation and differentiation of retinal progenitors.
6.
Zhu
Z, Khan MA, Weiler M, Blaes J, Jestaedt L, Geibert M, Zou P, Gronych J,
Bernhardt O, Korshunov A, Bugner V, Lichter P, Radlwimmer B, Heiland S,
Bendszus M, Wick W, Liu HK.
Cell Stem Cell. 2014 Aug 7;15(2):185-98. doi: 10.1016/j.stem.2014.04.007. Epub 2014 May 15.
Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx(+) cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx(+) cells can self-renew and generate Tlx(-) tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis.
Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx(+) cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx(+) cells can self-renew and generate Tlx(-) tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis.
7.
Qin S, Niu W, Iqbal N, Smith DK, Zhang CL.
Front Neurosci. 2014 Apr 10;8:74. doi: 10.3389/fnins.2014.00074. eCollection 2014.
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.
Figure 7. A schematic diagram illustrating the interplay
between TLX and the BMP-SMAD signaling pathway in the regulation of
neurogenesis and astrogenesis. TLX directly modulates the
expression of the BMP ligands, which bind and activate the type I (RI)
and type II (RII) receptors. These events result in phosphorylation of
regulatory SMADs and their dimerization with the common cofactor SMAD4.
The SMAD complex acts as a transcriptional activator to induce the
expression of downstream targets, which promote astrogenesis and inhibit
neurogenesis.
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.
FIGURE 7
Figure 7. A schematic diagram illustrating the interplay
between TLX and the BMP-SMAD signaling pathway in the regulation of
neurogenesis and astrogenesis. TLX directly modulates the
expression of the BMP ligands, which bind and activate the type I (RI)
and type II (RII) receptors. These events result in phosphorylation of
regulatory SMADs and their dimerization with the common cofactor SMAD4.
The SMAD complex acts as a transcriptional activator to induce the
expression of downstream targets, which promote astrogenesis and inhibit
neurogenesis.
8.
Xia J, Luo M, Ni N, Chen J, Hu Y, Deng Y, Ji J, Zhou J, Fan X, Gu P.
PLoS One. 2013 Sep 30;8(9):e76157. doi: 10.1371/journal.pone.0076157. eCollection 2013.
- Artikkeleita vuodelta 2013
9.
Chan CM, Fulton J, Montiel-Duarte C, Collins HM, Bharti N, Wadelin FR, Moran PM, Mongan NP, Heery DM.
Nucleic Acids Res. 2013 Nov;41(21):9663-79. doi: 10.1093/nar/gkt761. Epub 2013 Aug 23.
10.
Juárez P, Valdovinos MG, May ME, Lloyd BP, Couppis MH, Kennedy CH.
Behav Brain Res. 2013 Nov 1;256:354-61. doi: 10.1016/j.bbr.2013.07.044. Epub 2013 Aug 6.
11.
Ben Abdallah NM, Filipkowski RK, Pruschy M, Jaholkowski P, Winkler J, Kaczmarek L, Lipp HP.
Behav Brain Res. 2013 Sep 1;252:275-86. doi: 10.1016/j.bbr.2013.05.034. Epub 2013 May 25.
12.
Ryan SM, O'Keeffe GW, O'Connor C, Keeshan K, Nolan YM.
Brain Behav Immun. 2013 Oct;33:7-13. doi: 10.1016/j.bbi.2013.03.005. Epub 2013 Mar 16.
13.
Wang Y, Liu HK, Schütz G.
Mech Dev. 2013 Jun-Aug;130(6-8):388-90. doi: 10.1016/j.mod.2013.02.001. Epub 2013 Feb 13. Review.
Tailless (Tlx) is an orphan nuclear receptor
which is specifically expressed in the neural stem cells of the two
largest germinal neurogenesis zones in the adult mouse brain, the
subventricular zone (SVZ) of the lateral ventricle and the subgranular
zone (SGZ) of the dentate gyrus. By interacting with its cofactors, Tlx
represses its target genes and plays an important role in the
maintenance of adult NSCs. This review provides a snapshot of current
knowledge about Tlx function in adult NSCs.
14.
Zeng ZJ, Johansson E, Hayashi A, Chavali PL, Akrap N, Yoshida T, Kohno K, Izumi H, Funa K.
Biol Open. 2012 Jun 15;1(6):527-35. doi: 10.1242/bio.2012893. Epub 2012 Apr 18.
TLX is known as the orphan nuclear receptor
indispensable for maintaining neural stem cells in adult neurogenesis.
We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL), which stabilizes TLX. In turn, TLX
competes with hydroxylated hypoxia-inducible factor (HIF-α) for binding
to pVHL, which contributes to the stabilization of HIF-2α in
neuroblastoma during normoxia. Upon hypoxia, TLX
increases in the nucleus where it binds in close proximity of the
HIF-response element on the VEGF-promoter chromatin, and, together with
HIF-2α, recruits RNA polymerase II to induce VEGF expression.
Conversely, depletion of TLX
by shRNA decreases the expression of HIF-2α and VEGF as well as the
growth-promoting and colony-forming capacity of the neuroblastoma cell
lines IMR-32 and SH-SY5Y. On the contrary, silencing HIF-2α will
slightly increase TLX, suggesting that TLX acts to maintain a hypoxic environment when HIF-2α is decreasing. Our results demonstrate TLX to play a key role in controlling angiogenesis by regulating HIF-2α. TLX
and pVHL might counterbalance each other in important fate decisions
such as self-renewal and differentiation, as well as angiogenesis and
anti-angiogenesis.
- Artikkeleita vuodelta 2012
15.
Green HF, Nolan YM.
Transl Psychiatry. 2012 Nov 20;2:e194. doi: 10.1038/tp.2012.117.
Glycogen synthase kinase-3β (GSK-3β) and the orphan nuclear receptor tailless homolog (TLX) are key regulators of hippocampal neurogenesis, which has been reported to be dysregulated in both neurodegenerative and psychiatric disorders. Inflammation is also implicated in the neuropathology of these disorders because of increased levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the brain. At elevated levels, IL-1β signaling through the IL-1 receptor type 1 has been shown to be detrimental to hippocampal neurogenesis. TLX is required to maintain neural stem/progenitor cells (NSPCs) in an undifferentiated state and is involved in NSPC fate determination, while GSK-3β negatively regulates Wnt signaling, a vital pathway promoting neurogenesis. This study shows that GSK-3β inhibition using a small-molecule inhibitor and the mood stabilizer lithium restores the IL-1β-induced decrease in NSPC proliferation and neuronal differentiation of embryonic rat hippocampal NSPCs to control levels. The IL-1β-induced effect on NSPCs is paralleled by a decrease in TLX expression that can be prevented by GSK-3β inhibition. The present results suggest that GSK-3β ameliorates the anti-proliferative and pro-gliogenic effects of IL-1β, and that TLX is vulnerable to inflammatory insult. Strategies to reduce GSK-3β activity or to increase TLX expression may facilitate the restoration of hippocampal neurogenesis in neuroinflammatory conditions where neurogenesis is impaired.
Glycogen synthase kinase-3β (GSK-3β) and the orphan nuclear receptor tailless homolog (TLX) are key regulators of hippocampal neurogenesis, which has been reported to be dysregulated in both neurodegenerative and psychiatric disorders. Inflammation is also implicated in the neuropathology of these disorders because of increased levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the brain. At elevated levels, IL-1β signaling through the IL-1 receptor type 1 has been shown to be detrimental to hippocampal neurogenesis. TLX is required to maintain neural stem/progenitor cells (NSPCs) in an undifferentiated state and is involved in NSPC fate determination, while GSK-3β negatively regulates Wnt signaling, a vital pathway promoting neurogenesis. This study shows that GSK-3β inhibition using a small-molecule inhibitor and the mood stabilizer lithium restores the IL-1β-induced decrease in NSPC proliferation and neuronal differentiation of embryonic rat hippocampal NSPCs to control levels. The IL-1β-induced effect on NSPCs is paralleled by a decrease in TLX expression that can be prevented by GSK-3β inhibition. The present results suggest that GSK-3β ameliorates the anti-proliferative and pro-gliogenic effects of IL-1β, and that TLX is vulnerable to inflammatory insult. Strategies to reduce GSK-3β activity or to increase TLX expression may facilitate the restoration of hippocampal neurogenesis in neuroinflammatory conditions where neurogenesis is impaired.
16.
Zou Y, Niu W, Qin S, Downes M, Burns DK, Zhang CL.
Mol Cell Biol. 2012 Dec;32(23):4811-20. doi: 10.1128/MCB.01122-12. Epub 2012 Oct 1.
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.
17.
Li S, Sun G, Murai K, Ye P, Shi Y.
PLoS One. 2012;7(8):e43324. doi: 10.1371/journal.pone.0043324. Epub 2012 Aug 30.
18.
Weber KP, Alvaro CG, Baer GM, Reinert K, Cheng G, Clever S, Wightman B.
BMC Evol Biol. 2012 Jun 12;12:81. doi: 10.1186/1471-2148-12-81.
Estruch SB, Buzón V, Carbó LR, Schorova L, Lüders J, Estébanez-Perpiñá E.
PLoS One. 2012;7(6):e37963. doi: 10.1371/journal.pone.0037963. Epub 2012 Jun 4.
Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addition, we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunoprecipitation in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.
Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addition, we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunoprecipitation in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.
etc
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