TLX, an orphan nuclear receptor with emerging roles in physiology and disease

Endocrinology ◽  
2021 ◽  
Author(s):  
Adam T Nelson ◽  
Yu Wang ◽  
Erik R Nelson
Keyword(s):  
Nuclear Receptor ◽  
Therapeutic Target ◽  
Malignant Neoplasm ◽  
Orphan Nuclear Receptor ◽  
Endogenous Ligand ◽  
Diverse Range ◽  
Retinal Progenitor ◽  
Pathological Conditions ◽  
And Function ◽  
Abnormal Brain

Abstract TLX (NR2E1), an orphan member of the nuclear receptor superfamily, is a transcription factor that has been described to be generally repressive in nature. It has been implicated in several aspects of physiology and disease. TLX is best known for its ability to regulate the proliferation of neural stem cells and retinal progenitor cells. Dysregulation, overexpression, or loss of TLX expression has been characterized in numerous studies focused on a diverse range of pathological conditions, including: abnormal brain development, psychiatric disorders, retinopathies, metabolic disease, and malignant neoplasm. Despite the lack of an identified endogenous ligand, several studies have described putative synthetic and natural TLX ligands, suggesting that this receptor may serve as a therapeutic target. Therefore, this article aims to briefly review what is known about TLX structure and function in normal physiology, and provide an overview of TLX in regard to pathological conditions. Particular emphasis is placed on TLX and cancer, and the potential utility of this receptor as a therapeutic target.

scholarly journals Estrogen-related Receptor β (ERRβ) – Renaissance Receptor or Receptor Renaissance?

2016 ◽  
Vol 14 (1) ◽  
pp. nrs.14002 ◽  
Author(s):  
Shailaja D. Divekar ◽  
Deanna M. Tiek ◽  
Aileen Fernandez ◽  
Rebecca B. Riggins
Keyword(s):  
Alternative Splicing ◽  
Nuclear Receptor ◽  
Family Members ◽  
Structure And Function ◽  
The Other ◽  
Orphan Nuclear Receptor ◽  
Nuclear Receptor Superfamily ◽  
And Function ◽  
The Impact ◽  
Estrogen Related Receptor

Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα (ESRRA) and ERRγ (ESRRG) at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ (ESRRB), however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRβ in mouse, man, and other species, highlighting unique aspects of ERRβ biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.

scholarly journals Identification of an Endogenous Ligand Bound to a Native Orphan Nuclear Receptor

PLoS ONE ◽  
2009 ◽  
Vol 4 (5) ◽  
pp. e5609 ◽  
Author(s):  
Xiaohui Yuan ◽  
Tuong Chi Ta ◽  
Min Lin ◽  
Jane R. Evans ◽  
Yinchen Dong ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Orphan Nuclear Receptor ◽  
Endogenous Ligand

The role of the orphan nuclear receptor Rev-Erbα in adipocyte differentiation and function

Biochimie ◽  
2005 ◽  
Vol 87 (1) ◽  
pp. 21-25 ◽  
Author(s):  
S Laitinen ◽  
C Fontaine ◽  
JC Fruchart ◽  
B Staels
Keyword(s):  
Nuclear Receptor ◽  
Adipocyte Differentiation ◽  
Orphan Nuclear Receptor ◽  
And Function

Expression and function of orphan nuclear receptor TLX in adult neural stem cells

Nature ◽  
2004 ◽  
Vol 427 (6969) ◽  
pp. 78-83 ◽  
Author(s):  
Yanhong Shi ◽  
D. Chichung Lie ◽  
Philippe Taupin ◽  
Kinichi Nakashima ◽  
Jasodhara Ray ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Nuclear Receptor ◽  
Orphan Nuclear Receptor ◽  
Adult Neural Stem Cells ◽  
And Function

scholarly journals Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

2020 ◽  
Vol 21 (5) ◽  
pp. 1645 ◽  
Author(s):  
Madhulika Tripathi ◽  
Paul Michael Yen ◽  
Brijesh Kumar Singh
Keyword(s):  
Nuclear Receptor ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Cellular Metabolism ◽  
Orphan Nuclear Receptor ◽  
Receptor Alpha ◽  
Metabolic Genes ◽  
Mitochondrial Turnover ◽  
And Function ◽  
Estrogen Related Receptor

The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders.

scholarly journals Orphan Nuclear Receptor TR3/Nur77 is a Specific Therapeutic Target for Hepatic Cancers

2017 ◽  
Vol 06 (03) ◽  
Author(s):  
Yingling Zeng ◽  
Xiaoguang Ye ◽  
Degui Liao ◽  
Shizhang Huang ◽  
Huinan Mao ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Therapeutic Target ◽  
Orphan Nuclear Receptor

Structure and Function of the Atypical Orphan Nuclear Receptor Small Heterodimer Partner

2007 ◽  
pp. 117-158 ◽  
Author(s):  
Yong‐Soo Lee ◽  
Dipanjan Chanda ◽  
Jeonggu Sim ◽  
Yun‐Yong Park ◽  
Hueng‐Sik Choi
Keyword(s):  
Nuclear Receptor ◽  
Structure And Function ◽  
Orphan Nuclear Receptor ◽  
Small Heterodimer Partner ◽  
And Function

scholarly journals MEF2 Is Restricted to the Male Gonad and Regulates Expression of the Orphan Nuclear Receptor NR4A1

2014 ◽  
Vol 28 (6) ◽  
pp. 886-898 ◽  
Author(s):  
Caroline Daems ◽  
Luc J. Martin ◽  
Catherine Brousseau ◽  
Jacques J. Tremblay
Keyword(s):  
Nuclear Receptor ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Sex Differentiation ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Orphan Nuclear Receptor ◽  
Hormonal Stimulation ◽  
Regulatory Cascade ◽  
And Function

Abstract Leydig cell steroidogenesis is controlled by the pituitary gonadotropin LH that activates several signaling pathways, including the Ca2+/calmodulin kinase I (CAMKI) pathway. In other tissues, CAMKI regulates the activity of the myocyte enhancer factor 2 (MEF2) transcription factors. MEF2 factors are essential regulators of cell differentiation and organogenesis in numerous tissues but their expression and role in the mammalian gonad had not been explored. Here we show that MEF2 factors are expressed in a sexually dimorphic pattern in the mouse gonad. MEF2 factors are present in the testis throughout development and into adulthood but absent from the ovary. In the testis, MEF2 was localized mainly in the nucleus of both somatic lineages, the supporting Sertoli cells and the steroidogenic Leydig cells. In Leydig cells, MEF2 was found to activate the expression of Nr4a1, a nuclear receptor important for hormone-induced steroidogenesis. In these cells MEF2 also cooperates with forskolin and CAMKI to enhance Nr4a1 promoter activity via two MEF2 elements (−318 and −284 bp). EMSA confirmed direct binding of MEF2 to these elements whereas chromatin immunoprecipitation revealed that MEF2 recruitment to the proximal Nr4a1 promoter was increased following hormonal stimulation. Modulation of endogenous MEF2 protein level (small interfering RNA-mediated knockdown) or MEF2 activity (MEF2-Engrailed active dominant negative) led to a significant decrease in Nr4a1 mRNA levels in Leydig cells. All together, our results identify MEF2 as a novel testis-specific transcription factor, supporting a role for this factor in male sex differentiation and function. MEF2 was also positioned upstream of NR4A1 in a regulatory cascade controlling Leydig cell gene expression.

scholarly journals Regulation of sexually dimorphic abdominal courtship behaviors in Drosophila by the Tlx/tailless-like nuclear receptor, Dissatisfaction

2021 ◽  
Author(s):  
Julia C Duckhorn ◽  
Jessica Cande ◽  
Mary C Metkus ◽  
Hyeop Song ◽  
Sofia Altamirano ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Sexual Behaviors ◽  
Sexually Dimorphic ◽  
Orphan Nuclear Receptor ◽  
Female Development ◽  
The Central Nervous System ◽  
Courtship Behaviors ◽  
And Function ◽  
Male Specific ◽  
Necessary And Sufficient

Sexually dimorphic courtship behaviors in Drosophila melanogaster develop from the activity of the sexual differentiation genes, doublesex (dsx) and fruitless (fru), functioning with other regulatory factors that have received little attention. The dissatisfaction gene (dsf) encodes an orphan nuclear receptor homologous to vertebrate Tlx and Drosophila tailless that is critical for the development of several aspects of female- and male-specific sexual behaviors. Here, we report the pattern of dsf expression in the central nervous system and show that the activity of sexually dimorphic abdominal interneurons that co-express dsf and dsx is necessary and sufficient for vaginal plate opening in virgin females and abdominal curling in males during courtship. We find that dsf activity results in different neuroanatomical outcomes in females and males, promoting and suppressing, respectively, female development and function of the DDAG neurons depending upon the sexual state of dsx expression. We posit that dsf and dsx interact to specify sex differences in the neural circuitry for dimorphic abdominal behaviors.

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