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

Wang, Tao; Xiong, Jie

doi:10.1007/s12264-015-0004-7

Cited by 17 publications

(10 citation statements)

References 74 publications

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“…These observations indicate that these disease-associated genes might become deregulated during development due to mutations altering the functionality of FOXP1 or changes in its expression levels ( Chien et al., 2013 , Lozano et al., 2015 ). In our ChIP-seq analysis, we found the consensus motives of the neurodevelopmental transcription factors SOX3 and NR2E1/TLX associated with the Forkhead motif ( Archer et al., 2011 , Wang and Xiong, 2016 ), indicating a possible interaction between FOXP1 and these factors to regulate genes involved in neurogenesis. SOX3 inhibits neural progenitor differentiation by preventing premature activation of neuronal genes by competing for binding sites with SOX11 ( Bergsland et al., 2011 ).…”

Section: Discussionmentioning

confidence: 84%

FOXP1 Promotes Embryonic Neural Stem Cell Differentiation by Repressing Jagged1 Expression

et al. 2017

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SummaryMutations in FOXP1 have been linked to neurodevelopmental disorders including intellectual disability and autism; however, the underlying molecular mechanisms remain ill-defined. Here, we demonstrate with RNA and chromatin immunoprecipitation sequencing that FOXP1 directly regulates genes controlling neurogenesis. We show that FOXP1 is expressed in embryonic neural stem cells (NSCs), and modulation of FOXP1 expression affects both neuron and astrocyte differentiation. Using a murine model of cortical development, FOXP1-knockdown in utero was found to reduce NSC differentiation and migration during corticogenesis. Furthermore, transplantation of FOXP1-knockdown NSCs in neonatal mice after hypoxia-ischemia challenge demonstrated that FOXP1 is also required for neuronal differentiation and functionality in vivo. FOXP1 was found to repress the expression of Notch pathway genes including the Notch-ligand Jagged1, resulting in inhibition of Notch signaling. Finally, blockade of Jagged1 in FOXP1-knockdown NSCs rescued neuronal differentiation in vitro. Together, these data support a role for FOXP1 in regulating embryonic NSC differentiation by modulating Notch signaling.

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Section: Discussionmentioning

confidence: 84%

FOXP1 Promotes Embryonic Neural Stem Cell Differentiation by Repressing Jagged1 Expression

et al. 2017

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“…Recent attention has focused on the role of some nuclear receptors (e.g. Nr2e1 and REV‐ERBα) in regulating neurogenesis (Islam & Zhang ; Li et al ; Qu & Shi ; Schnell et al ; Shi et al ; Wang & Xiong ; Wang et al ). In an effort to further understand the role of Tlx in neural development and behaviour, several different Tlx deletion models have been developed in mice (Monaghan et al ; Shi et al ; Young et al ; Yu et al ; Zhang et al ).…”

Section: Summary Of Neuroanatomical Changes Across Strain Backgroundsmentioning

confidence: 99%

Regulation of behaviour by the nuclear receptor TLX

O’Leary

Cryan

et al. 2016

Genes Brain and Behavior

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The orphan nuclear receptor Tlx (Nr2e1) is a key regulator of both embryonic and adult hippocampal neurogenesis. Several different mouse models have been developed which target Tlx in vivo including spontaneous deletion models (from birth) and targeted and conditional knockouts. Although some conflicting findings have been reported, for the most part studies have demonstrated that Tlx is important in regulating processes that underlie neurogenesis, spatial learning, anxiety-like behaviour and interestingly, aggression. More recent data have demonstrated that disrupting Tlx during early life induces hyperactivity and that Tlx plays a role in emotional regulation. Moreover, there are sex- and age-related differences in some behaviours in Tlx knockout mice during adolescence and adulthood. Here, we discuss the role of Tlx in motor-, cognitive-, aggressive- and anxiety-related behaviours during adolescence and adulthood. We examine current evidence which provides insight into Tlx during neurodevelopment, and offer our thoughts on the function of Tlx in brain and behaviour. We further hypothesize that Tlx is a key target in understanding the emergence of neurobiological disorders during adolescence and early adulthood.

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“…TLX ( NR2E1 ) is an orphan nuclear receptor belonging to the nuclear receptor superfamily. Studies in past decades indicate that TLX plays important roles in brain and retina development, maintenance of stemness, and self-renewal of embryonic and adult neural stem cells (NSCs) via its direct transcriptional control of genes involved in DNA replication, cell cycle, adhesion, and migration, Wnt/α-catenin, and mitogen-activated protein kinase (MAPK) signaling [ 21 , 22 ]. Its dysregulation is implicated in several neurological disorders [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription

Jia

Wang

et al. 2018

Oncogene

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The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

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

Cited by 17 publications

References 74 publications

FOXP1 Promotes Embryonic Neural Stem Cell Differentiation by Repressing Jagged1 Expression

FOXP1 Promotes Embryonic Neural Stem Cell Differentiation by Repressing Jagged1 Expression

Regulation of behaviour by the nuclear receptor TLX

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription

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