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1
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Chow ST, Fan J, Zhang X, Wang Y, Li Y, Ng CF, Pei X, Zheng Q, Wang F, Wu D, Chan FL. Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors. Br J Cancer 2024; 131:1450-1462. [PMID: 39322688 PMCID: PMC11519473 DOI: 10.1038/s41416-024-02843-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 09/27/2024] Open
Abstract
BACKGROUND Prostate cancer stem cells (PCSCs) play crucial roles in therapy-resistance and metastasis in castration-resistant prostate cancer (CRPC). Certain functional link between cancer stemness and epithelial-mesenchymal transition (EMT) is involved in CRPC. However, up-stream regulators controlling these two processes in PCSCs are still poorly understood. Recently, we have shown that orphan nuclear receptor TLX can promote tumour initiation and progression in CRPC by repressing androgen receptor and oncogene-induced senescence. METHODS PCSCs were isolated from various prostate cancer cell lines and clinical tumour tissues using multiple methods for various in vitro and in vivo oncogenic growth analyses. Direct targets of TLX involved in stemness and EMT regulation were determined by specific reporter gene assays and ligand-driven modulation of TLX activity. RESULTS PCSCs isolated from various sources exhibited increased expression of TLX. Functional and molecular characterisation showed that TLX could function to promote cancer stemness and EMT in prostate cancer cells via its direct transactivation of CD44, SOX2, POU5F1 and NANOG, which share certain functional crosstalk in these two cellular processes. CONCLUSIONS TLX could act as a key up-stream regulator in transcriptional control of stemness and EMT in PCSCs, which contribute to their tumorigenicity, castration-resistance and metastasis potentials in advanced prostate cancer.
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Affiliation(s)
- Sin Ting Chow
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Jiaqi Fan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Xingxing Zhang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Yuliang Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Youjia Li
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Chi-Fai Ng
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Xiaojuan Pei
- Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guandong, China
| | - Qingyou Zheng
- Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong Province, China
| | - Fei Wang
- Department of Urology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
| | - Dinglan Wu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
- Department of Urology and The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China.
| | - Franky Leung Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
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2
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Masuda LHP, Sabino AU, Reinitz J, Ramos AF, Machado-Lima A, Andrioli LP. Global repression by tailless during segmentation. Dev Biol 2024; 505:11-23. [PMID: 37879494 PMCID: PMC10949167 DOI: 10.1016/j.ydbio.2023.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023]
Abstract
The orphan nuclear receptor Tailless (Tll) exhibits conserved roles in brain formation and maintenance that are shared, for example, with vertebrate orthologous forms (Tlx). However, the early expression of tll in two gap domains in the segmentation cascade of Drosophila is unusual even for most other insects. Here we investigate tll regulation on pair-rule stripes. With ectopic misexpression of tll we detected unexpected repression of almost all pair-rule stripes of hairy (h), even-skipped (eve), runt (run), and fushi-tarazu (ftz). Examining Tll embryonic ChIP-chip data with regions mapped as Cis-Regulatory Modules (CRMs) of pair-rule stripes we verified Tll interactions to these regions. With the ChIP-chip data we also verified Tll interactions to the CRMs of gap domains and in the misexpression assay, Tll-mediated repression on Kruppel (Kr), kni (kni) and giant (gt) according to their differential sensitivity to Tll. These results with gap genes confirmed previous data from the literature and argue against indirect repression roles of Tll in the striped pattern. Moreover, the prediction of Tll binding sites in the CRMs of eve stripes and the mathematical modeling of their removal using an experimentally validated theoretical framework shows effects on eve stripes compatible with the absence of a repressor binding to the CRMs. In addition, modeling increased tll levels in the embryo results in the differential repression of eve stripes, agreeing well with the results of the misexpression assay. In genetic assays we investigated eve 5, that is strongly repressed by the ectopic domain and representative of more central stripes not previously implied to be under direct regulation of tll. While this stripe is little affected in tll-, its posterior border is expanded in gt- but detected with even greater expansion in gt-;tll-. We end up by discussing tll with key roles in combinatorial repression mechanisms to contain the expression of medial patterns of the segmentation cascade in the extremities of the embryo.
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Affiliation(s)
| | - Alan Utsuni Sabino
- Departamento de Radiologia e Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - John Reinitz
- Departments of Statistics, Ecology and Evolution, Molecular Genetics & Cell Biology, Institute of Genomics and Systems Biology, University of Chicago, Chicago, IL, USA
| | | | - Ariane Machado-Lima
- Escola de Artes, Ciências e Humanidades da Universidade de São Paulo, São Paulo, Brazil
| | - Luiz Paulo Andrioli
- Escola de Artes, Ciências e Humanidades da Universidade de São Paulo, São Paulo, Brazil.
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3
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Wang M, Yang Y, Xu Y. Brain nuclear receptors and cardiovascular function. Cell Biosci 2023; 13:14. [PMID: 36670468 PMCID: PMC9854230 DOI: 10.1186/s13578-023-00962-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/12/2023] [Indexed: 01/22/2023] Open
Abstract
Brain-heart interaction has raised up increasing attentions. Nuclear receptors (NRs) are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of cardiovascular diseases (CVDs), including hypertension, heart failure, atherosclerosis, etc. In this review, we will elaborate recent findings that have established the physiological relevance of brain NRs in the context of cardiovascular function. In addition, we will discuss the currently available evidence regarding the distinct neuronal populations that respond to brain NRs in the cardiovascular control. These findings suggest connections between cardiac control and brain dynamics through NR signaling, which may lead to novel tools for the treatment of pathological changes in the CVDs.
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Affiliation(s)
- Mengjie Wang
- Department of Pediatrics, USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX USA
| | - Yongjie Yang
- Department of Pediatrics, USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX USA
| | - Yong Xu
- Department of Pediatrics, USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX USA
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4
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Duan LJ, Jiang Y, Shi Y, Fong GH. Tailless and hypoxia inducible factor-2α cooperate to sustain proangiogenic states of retinal astrocytes in neonatal mice. Biol Open 2023; 12:286421. [PMID: 36625299 PMCID: PMC9867894 DOI: 10.1242/bio.059684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 10/31/2022] [Indexed: 01/11/2023] Open
Abstract
Tailless (TLX, an orphan nuclear receptor) and hypoxia inducible factor-2α (HIF2α) are both essential for retinal astrocyte and vascular development. Tlx-/- mutation and astrocyte specific Hif2α disruption in Hif2αf/f/GFAPCre mice are known to cause defective astrocyte development and block vascular development in neonatal retinas. Here we report that TLX and HIF2α support retinal angiogenesis by cooperatively maintaining retinal astrocytes in their proangiogenic states. While Tlx+/- and Hif2αf/+/GFAPCre mice are phenotypically normal, Tlx+/-/Hif2αf/+/GFAPCre mice display precocious retinal astrocyte differentiation towards non-angiogenic states, along with significantly reduced retinal angiogenesis. In wild-type mice, TLX and HIF2α coexist in the same protein complex, suggesting a cooperative function under physiological conditions. Furthermore, astrocyte specific disruption of Phd2 (prolyl hydroxylase domain protein 2), a manipulation previously shown to cause HIF2α accumulation, did not rescue retinal angiogenesis in Tlx-/- background, which suggests functional dependence of HIF2α on TLX. Finally, the expression of fibronectin and VEGF-A is significantly reduced in retinal astrocytes of neonatal Tlx+/-/Hif2αf/+/GFAPCre mice. Overall, these data indicate that TLX and HIF2α cooperatively support retinal angiogenesis by maintaining angiogenic potential of retinal astrocytes.
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Affiliation(s)
- Li-Juan Duan
- Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
| | - Yida Jiang
- Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA,Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA
| | - Yanhong Shi
- Department of Stem Cell Biology and Regenerative Medicine, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Guo-Hua Fong
- Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA,Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA,Author for correspondence ()
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5
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Morini E, Gao D, Logan EM, Salani M, Krauson AJ, Chekuri A, Chen YT, Ragavendran A, Chakravarty P, Erdin S, Stortchevoi A, Svejstrup JQ, Talkowski ME, Slaugenhaupt SA. Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage. J Genet Genomics 2022; 49:654-665. [PMID: 34896608 PMCID: PMC9254147 DOI: 10.1016/j.jgg.2021.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/27/2021] [Accepted: 11/04/2021] [Indexed: 01/21/2023]
Abstract
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1-/-) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.
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Affiliation(s)
- Elisabetta Morini
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA
| | - Dadi Gao
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Emily M Logan
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Monica Salani
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Aram J Krauson
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Anil Chekuri
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA
| | - Yei-Tsung Chen
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taiwan
| | - Ashok Ragavendran
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Probir Chakravarty
- Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK
| | - Serkan Erdin
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Alexei Stortchevoi
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jesper Q Svejstrup
- Mechanisms of Transcription Laboratory, The Francis Crick Institute, London, UK; Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Michael E Talkowski
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Susan A Slaugenhaupt
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.
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6
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Oleic acid regulates hippocampal neurogenesis as a TLX ligand. Proc Natl Acad Sci U S A 2022; 119:e2203038119. [PMID: 35344400 PMCID: PMC9169763 DOI: 10.1073/pnas.2203038119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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7
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Chen R, Deng X, Zhu S. The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless. PLoS Genet 2022; 18:e1009928. [PMID: 35100262 PMCID: PMC8830786 DOI: 10.1371/journal.pgen.1009928] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/10/2022] [Accepted: 01/20/2022] [Indexed: 12/03/2022] Open
Abstract
Intermediate neural progenitors (INPs) boost the number and diversity of neurons generated from neural stem cells (NSCs) by undergoing transient proliferation. In the developing Drosophila brains, INPs are generated from type II neuroblasts (NBs). In order to maintain type II NB identity and their capability to produce INPs, the proneural protein Asense (Ase) needs to be silenced by the Ets transcription factor pointed P1 (PntP1), a master regulator of type II NB development. However, the molecular mechanisms underlying the PntP1-mediated suppression of Ase is still unclear. In this study, we utilized genetic and molecular approaches to determine the transcriptional property of PntP1 and identify the direct downstream effector of PntP1 and the cis-DNA elements that mediate the suppression of ase. Our results demonstrate that PntP1 directly activates the expression of the transcriptional repressor, Tailless (Tll), by binding to seven Ets-binding sites, and Tll in turn suppresses the expression of Ase in type II NBs by binding to two hexameric core half-site motifs. We further show that Tll provides positive feedback to maintain the expression of PntP1 and the identity of type II NBs. Thus, our study identifies a novel direct target of PntP1 and reveals mechanistic details of the specification and maintenance of the type II NB identity by PntP1. Type II neuroblasts (NBs) are the neural stem cells (NSCs) in Drosophila central brains that produce neurons by generating intermediate neural progenitors (INPs) to boost brain complexity, as mammalian NSCs do during the development of neocortex. The key to the generation of INPs from type II NBs is the suppression of proneural protein Asense (Ase) in type II NBs by the Ets family transcription factor Pointed P1 (PntP1), but how PntP1 suppresses Ase expression remains unclear. In this study, we provided evidence to demonstrate that PntP1 directly activates the orphan nuclear receptor Tailless (Tll), which in turn suppresses Ase expression to maintain the capability of type II NBs to produce INPs. Meanwhile, Tll provides positive feedback to maintain the expression of PntP1 and type II NB identity. We further identified seven PntP1 binding sites in the tll enhancer regions and two Tll binding sites in the ase regulatory regions that mediate the activation of tll and the suppression of ase, respectively. Our work reveals detailed mechanisms of the specification and maintenance of the type II NB identity by PntP1.
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Affiliation(s)
- Rui Chen
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, United States of America
| | - Xiaobing Deng
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, United States of America
| | - Sijun Zhu
- Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, United States of America
- * E-mail:
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8
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Nelson AT, Wang Y, Nelson ER. TLX, an Orphan Nuclear Receptor With Emerging Roles in Physiology and Disease. Endocrinology 2021; 162:6360449. [PMID: 34463725 PMCID: PMC8462384 DOI: 10.1210/endocr/bqab184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Indexed: 12/14/2022]
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.
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Affiliation(s)
- Adam T Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Yu Wang
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60612, USA
- Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA
- Correspondence: Erik R. Nelson, PhD, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 407 S Goodwin Ave (MC-114), Urbana, IL 61801, USA.
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9
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Majidi S, Ogilvie JM, Flaveny CA. Retinal Degeneration: Short-Term Options and Long-Term Vision for Future Therapy. MISSOURI MEDICINE 2021; 118:466-472. [PMID: 34658442 PMCID: PMC8504501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
The leading cause blindness is the loss of retinal ganglion cells which connect the retina to the brain. Degenerative retinal diseases include retinal dystrophy, macular degeneration and diabetic retinopathy, which are currently incurable as the mammalian retina has no intrinsic regenerative capacity. By utilizing insight gained from retinal regeneration in simpler species we define an approach that may unlock regenerative programs in the mammalian retina that potentially facilitate the clinical restoration of retinal function.
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Affiliation(s)
- Shabnam Majidi
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Judith M Ogilvie
- Department of Biology; Saint Louis University School of Medicine, St. Louis, Missouri
| | - Colin A Flaveny
- Department of Biology; Saint Louis University School of Medicine, St. Louis, Missouri
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Wu W, LoVerde PT. Identification and evolution of nuclear receptors in Platyhelminths. PLoS One 2021; 16:e0250750. [PMID: 34388160 PMCID: PMC8363021 DOI: 10.1371/journal.pone.0250750] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/18/2021] [Indexed: 11/24/2022] Open
Abstract
Since the first complete set of Platyhelminth nuclear receptors (NRs) from Schistosoma mansoni were identified a decade ago, more flatworm genome data is available to identify their NR complement and to analyze the evolutionary relationship of Platyhelminth NRs. NRs are important transcriptional modulators that regulate development, differentiation and reproduction of animals. In this study, NRs are identified in genome databases of thirty-three species including in all Platyhelminth classes (Rhabditophora, Monogenea, Cestoda and Trematoda). Phylogenetic analysis shows that NRs in Platyhelminths follow two different evolutionary lineages: 1) NRs in a free-living freshwater flatworm (Schmidtea mediterranea) and all parasitic flatworms share the same evolutionary lineage with extensive gene loss. 2) NRs in a free-living intertidal zone flatworm (Macrostomum lignano) follow a different evolutionary lineage with a feature of multiple gene duplication and gene divergence. The DNA binding domain (DBD) is the most conserved region in NRs which contains two C4-type zinc finger motifs. A novel zinc finger motif is identified in parasitic flatworm NRs: the second zinc finger of parasitic Platyhelminth HR96b possesses a CHC2 motif which is not found in NRs of all other animals studied to date. In this study, novel NRs (members of NR subfamily 3 and 6) are identified in flatworms, this result demonstrates that members of all six classical NR subfamilies are present in the Platyhelminth phylum. NR gene duplication, loss and divergence in Platyhelminths are analyzed along with the evolutionary relationship of Platyhelminth NRs.
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Affiliation(s)
- Wenjie Wu
- Departments of Biochemistry and Structural Biology and Pathology and Laboratory Medicine, University of Texas Health Sciences Center, San Antonio, Texas, United States of America
| | - Philip T. LoVerde
- Departments of Biochemistry and Structural Biology and Pathology and Laboratory Medicine, University of Texas Health Sciences Center, San Antonio, Texas, United States of America
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11
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He G, Gu J, Wang H, Cheng S, Xiong Q, Ke M, Hu Y, Feng J, Song L, Liu Z, Xu Y. Nr2e1 deficiency aggravates insulin resistance and chronic inflammation of visceral adipose tissues in a diet-induced obese mice model. Life Sci 2021; 278:119562. [PMID: 33915130 DOI: 10.1016/j.lfs.2021.119562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/11/2021] [Accepted: 04/23/2021] [Indexed: 10/21/2022]
Abstract
AIMS To investigate the nuclear receptor subfamily 2 group E member 1 (Nr2e1) expression in adipose tissues of obese mice and assess the role of Nr2e1 in insulin resistance and chronic inflammation of the adipose tissues. MAIN METHODS An obese model was established in Nr2e1 knockout (KO) mice and their wild type (WT) littermates through a long-term high-fat diet (HFD) feeding regime. The epididymal fat weight, body weight, and daily food intake were recorded. The blood lipid profile, blood inflammatory factors, and the levels of fasting blood glucose (FBG) and fasting insulin were determined. We estimated insulin resistance by the homeostasis model assessment (HOMA). The expression of inflammatory factors and F4/80 was examined by polymerase chain reaction (PCR) and western blotting to assess adipose tissues inflammation. We also determined the molecules of insulin signaling and the nuclear factor kappa B (NF-κB) pathway by western blotting. KEY FINDINGS The Nr2e1 expression was upregulated in WT obese mice when compared with that in control mice. Despite a lower body weight and epididymal fat mass in Nr2e1-/- mice, these rats showed increased inflammatory cytokines secretion, more pronounced hyperlipidemia, and impaired insulin sensitivity after HFD treatment. Further investigation revealed that Nr2e1 deletion affected the expression of insulin signaling and NF-κB pathway-related molecules in visceral adipose tissues. SIGNIFICANCE Nr2e1 may act as a potential target to improve insulin sensitivity and inflammation in obesity and related complications.
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Affiliation(s)
- Guangzhen He
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Department of Pediatrics, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, Hubei, China
| | - Jiaowei Gu
- Department of Pediatrics, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, Hubei, China
| | - Huawei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Siyuan Cheng
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Qing Xiong
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Mengting Ke
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yong Hu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Jieyuan Feng
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Linyang Song
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Zheng Liu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Yancheng Xu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
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12
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Griffett K, Bedia-Diaz G, Hegazy L, de Vera IMS, Wanninayake US, Billon C, Koelblen T, Wilhelm ML, Burris TP. The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids. Cell Chem Biol 2020; 27:1272-1284.e4. [DOI: 10.1016/j.chembiol.2020.07.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/08/2020] [Accepted: 07/17/2020] [Indexed: 12/13/2022]
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13
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Parris TZ, Vizlin-Hodzic D, Salmela S, Funa K. Tumorigenic effects of TLX overexpression in HEK 293T cells. Cancer Rep (Hoboken) 2020; 2:e1204. [PMID: 32721119 DOI: 10.1002/cnr2.1204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/28/2019] [Accepted: 06/04/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The human orphan receptor TLX (NR2E1) is a key regulator of neurogenesis, adult stem cell maintenance, and tumorigenesis. However, little is known about the genetic and transcriptomic events that occur following TLX overexpression in human cell lines. AIMS Here, we used cytogenetics and RNA sequencing to investigate the effect of TLX overexpression with an inducible vector system in the HEK 293T cell line. METHODS AND RESULTS Conventional spectral karyotyping was used to identify chromosomal abnormalities, followed by fluorescence in situ hybridization (FISH) analysis on chromosome spreads to assess TLX DNA copy number. Illumina paired-end whole transcriptome sequencing was then performed to characterize recurrent genetic variants (single nucleotide polymorphisms (SNPs) and indels), expressed gene fusions, and gene expression profiles. Lastly, flow cytometry was used to analyze cell cycle distribution. Intriguingly, we show that upon transfection with a vector containing the human TLX gene (eGFP-hTLX), an isochromosome forms on the long arm of chromosome 6, thereby resulting in DNA gain of the TLX locus (6q21) and upregulation of TLX. Induction of the eGFP-hTLX vector further increased TLX expression levels, leading to G0-G1 cell cycle arrest, genetic aberrations, modulation of gene expression patterns, and crosstalk with other nuclear receptors (AR, ESR1, ESR2, NR1H4, and NR3C2). We identified a 49-gene signature associated with central nervous system (CNS) development and carcinogenesis, in addition to potentially cancer-driving gene fusions (LARP1-CNOT8 and NSL1-ZDBF2) and deleterious genetic variants (frameshift insertions in the CTSH, DBF4, POSTN, and WDR78 genes). CONCLUSION Taken together, these findings illustrate that TLX may play a pivotal role in tumorigenesis via genomic instability and perturbation of cancer-related processes.
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Affiliation(s)
- Toshima Z Parris
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Dzeneta Vizlin-Hodzic
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Susanne Salmela
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Keiko Funa
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
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14
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Hakes AE, Brand AH. Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ASCL1. eLife 2020; 9:e53377. [PMID: 32073402 PMCID: PMC7058384 DOI: 10.7554/elife.53377] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/19/2020] [Indexed: 02/06/2023] Open
Abstract
Understanding the sequence of events leading to cancer relies in large part upon identifying the tumour cell of origin. Glioblastoma is the most malignant brain cancer but the early stages of disease progression remain elusive. Neural lineages have been implicated as cells of origin, as have glia. Interestingly, high levels of the neural stem cell regulator TLX correlate with poor patient prognosis. Here we show that high levels of the Drosophila TLX homologue, Tailless, initiate tumourigenesis by reverting intermediate neural progenitors to a stem cell state. Strikingly, we could block tumour formation completely by re-expressing Asense (homologue of human ASCL1), which we show is a direct target of Tailless. Our results predict that expression of TLX and ASCL1 should be mutually exclusive in glioblastoma, which was verified in single-cell RNA-seq of human glioblastoma samples. Counteracting high TLX is a potential therapeutic strategy for suppressing tumours originating from intermediate progenitor cells.
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Affiliation(s)
- Anna E Hakes
- The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of CambridgeCambridgeUnited Kingdom
| | - Andrea H Brand
- The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of CambridgeCambridgeUnited Kingdom
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15
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Xiong Q, Wu Y, Yang M, Wu G, Wang Y, Wang H, Feng J, Song L, Tong B, He G, Xu Y. Nr2e1 ablation impairs liver glucolipid metabolism and induces inflammation, high-fat diets amplify the damage. Biomed Pharmacother 2019; 120:109503. [DOI: 10.1016/j.biopha.2019.109503] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/17/2019] [Accepted: 09/26/2019] [Indexed: 02/08/2023] Open
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16
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Luque-Molina I, Shi Y, Abdullah Y, Monaco S, Hölzl-Wenig G, Mandl C, Ciccolini F. The Orphan Nuclear Receptor TLX Represses Hes1 Expression, Thereby Affecting NOTCH Signaling and Lineage Progression in the Adult SEZ. Stem Cell Reports 2019; 13:132-146. [PMID: 31178417 PMCID: PMC6626847 DOI: 10.1016/j.stemcr.2019.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 05/06/2019] [Accepted: 05/06/2019] [Indexed: 12/31/2022] Open
Abstract
In the adult subependymal zone (SEZ), neural stem cells (NSCs) apically contacting the lateral ventricle on activation generate progenitors proliferating at the niche basal side. We here show that Tailless (TLX) coordinates NSC activation and basal progenitor proliferation by repressing the NOTCH effector Hes1. Consistent with this, besides quiescence Hes1 expression also increases on Tlx mutation. Since HES1 levels are higher at the apical SEZ, NOTCH activation is increased in Tlx−/− NSCs, but not in surrounding basal progenitors. Underscoring the causative relationship between higher HES1/NOTCH and increased quiescence, downregulation of Hes1 only in mutant NSCs normalizes NOTCH activation and resumes proliferation and neurogenesis not only in NSCs, but especially in basal progenitors. Since pharmacological blockade of NOTCH signaling also promotes proliferation of basal progenitors, we conclude that TLX, by repressing Hes1 expression, counteracts quiescence and NOTCH activation in NSCs, thereby relieving NOTCH-mediated lateral inhibition of proliferation in basal progenitors.
TLX autonomously controls quiescence in apical NSCs by repressing Hes1 TLX controls basal progenitor proliferation via NOTCH-mediated lateral inhibition Downregulation of Hes1 in apical Tlx−/− NSCs resumes proliferation and neurogenesis
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Affiliation(s)
- Inma Luque-Molina
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Yan Shi
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Yomn Abdullah
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Sara Monaco
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Gabriele Hölzl-Wenig
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Claudia Mandl
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Francesca Ciccolini
- Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
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17
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Abdolmaleky HM, Gower AC, Wong CK, Cox JW, Zhang X, Thiagalingam A, Shafa R, Sivaraman V, Zhou JR, Thiagalingam S. Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2019; 180:138-149. [PMID: 30468562 PMCID: PMC6386618 DOI: 10.1002/ajmg.b.32691] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 07/23/2018] [Accepted: 09/18/2018] [Indexed: 12/15/2022]
Abstract
Although the loss of brain laterality is one of the most consistent modalities in schizophrenia (SCZ) and bipolar disorder (BD), its molecular basis remains elusive. Our limited previous studies indicated that epigenetic modifications are key to the asymmetric transcriptomes of brain hemispheres. We used whole-genome expression microarrays to profile postmortem brain samples from subjects with SCZ, psychotic BD [BD[+]] or non-psychotic BD [BD(-)], or matched controls (10/group) and performed whole-genome DNA methylation (DNAM) profiling of the same samples (3-4/group) to identify pathways associated with SCZ or BD[+] and genes/sites susceptible to epigenetic regulation. qRT-PCR and quantitative DNAM analysis were employed to validate findings in larger sample sets (35/group). Gene Set Enrichment Analysis (GSEA) demonstrated that BMP signaling and astrocyte and cerebral cortex development are significantly (FDR q < 0.25) coordinately upregulated in both SCZ and BD[+], and glutamate signaling and TGFβ signaling are significantly coordinately upregulated in SCZ. GSEA also indicated that collagens are downregulated in right versus left brain of controls, but not in SCZ or BD[+] patients. Ingenuity Pathway Analysis predicted that TGFB2 is an upstream regulator of these genes (p = .0012). While lateralized expression of TGFB2 in controls (p = .017) is associated with a corresponding change in DNAM (p ≤ .023), lateralized expression and DNAM of TGFB2 are absent in SCZ or BD. Loss of brain laterality in SCZ and BD corresponds to aberrant epigenetic regulation of TGFB2 and changes in TGFβ signaling, indicating potential avenues for disease prevention/treatment.
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Affiliation(s)
- Hamid Mostafavi Abdolmaleky
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA,Nutrition/Metabolism Laboratory, BIDMC, Harvard Medical School, Boston, MA,Corresponding Authors: Hamid Mostafavi Abdolmaleky () and Sam Thiagalingam ()
| | - Adam Chapin Gower
- Clinical and Translational Science Institute, Boston University School of Medicine, Boston, MA
| | - Chen Khuan Wong
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA,Genetics & Genomics Graduate Program, Boston University School of Medicine, Boston, MA
| | - Jiayi Wu Cox
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA,Bioinformatics Graduate Program, Boston University, Boston, MA
| | - Xiaoling Zhang
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA
| | - Arunthathi Thiagalingam
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA
| | | | - Vadivelu Sivaraman
- Critical Care Medicine, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD
| | - Jin-Rong Zhou
- Nutrition/Metabolism Laboratory, BIDMC, Harvard Medical School, Boston, MA
| | - Sam Thiagalingam
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA,Genetics & Genomics Graduate Program, Boston University School of Medicine, Boston, MA,Department of Pathology & Laboratory Medicine, Boston University School of Medicine, Boston, MA,Corresponding Authors: Hamid Mostafavi Abdolmaleky () and Sam Thiagalingam ()
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18
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Kozareva DA, Foley T, Moloney GM, Cryan JF, Nolan YM. TLX knockdown in the dorsal dentate gyrus of juvenile rats differentially affects adolescent and adult behaviour. Behav Brain Res 2018; 360:36-50. [PMID: 30481511 DOI: 10.1016/j.bbr.2018.11.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 11/23/2018] [Accepted: 11/23/2018] [Indexed: 12/27/2022]
Abstract
The orphan nuclear receptor TLX is predominantly expressed in the central nervous system and is an important factor regulating the maintenance and self-renewal of neural stem cells from embryonic development through adulthood. In adolescence and adulthood, TLX expression is restricted to the neurogenic niches of the brain: the dentate gyrus of the hippocampus and the subventricular zone. The adolescent period is critical for maturation of the hippocampus with heightened levels of neurogenesis observed in rodents. Therefore, we investigated whether lentiviral silencing of TLX expression (TLX knockdown) in the dorsal dentate gyrus of juvenile rats incurred differential impairments in behaviour during late adolescence and adulthood. Our results showed that knockdown of TLX in the dorsal dentate gyrus led to a decrease in cell proliferation in the dorsal but not ventral dentate gyrus. At a behavioural level we observed differential effects in adolescence and adulthood across a number of parameters. A hyperactive phenotype was present in adolescent but not adult TLX knockdown rats, and an increase in immobility during adolescence and in swimming frequency during adulthood was observed in the forced swim test. There was an increased defecation frequency in the open field during adulthood but not adolescence. There were no changes in cognitive performance on hippocampus-dependent tasks or in anxiety-related behaviours. In conclusion, silencing of TLX in the dorsal dentate gyrus led to impairments in hippocampal-independent behaviours which either did not persist or were reversed during adulthood. The current data highlight the temporal importance and function of the nuclear receptor TLX during development.
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Affiliation(s)
- Danka A Kozareva
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - Tara Foley
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - Gerard M Moloney
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Yvonne M Nolan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland.
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19
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Dueva E, Singh K, Kalyta A, LeBlanc E, Rennie PS, Cherkasov A. Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor. Molecules 2018; 23:molecules23112967. [PMID: 30441799 PMCID: PMC6278398 DOI: 10.3390/molecules23112967] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 11/01/2018] [Accepted: 11/09/2018] [Indexed: 12/17/2022] Open
Abstract
Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40–50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 µM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.
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Affiliation(s)
- Evgenia Dueva
- Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
| | - Kriti Singh
- Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
| | - Anastasia Kalyta
- Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
| | - Eric LeBlanc
- Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
| | - Paul S Rennie
- Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
| | - Artem Cherkasov
- Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
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20
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Gkikas D, Tsampoula M, Politis PK. Nuclear receptors in neural stem/progenitor cell homeostasis. Cell Mol Life Sci 2017; 74:4097-4120. [PMID: 28638936 PMCID: PMC11107725 DOI: 10.1007/s00018-017-2571-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 06/06/2017] [Accepted: 06/13/2017] [Indexed: 12/13/2022]
Abstract
In the central nervous system, embryonic and adult neural stem/progenitor cells (NSCs) generate the enormous variety and huge numbers of neuronal and glial cells that provide structural and functional support in the brain and spinal cord. Over the last decades, nuclear receptors and their natural ligands have emerged as critical regulators of NSC homeostasis during embryonic development and adult life. Furthermore, substantial progress has been achieved towards elucidating the molecular mechanisms of nuclear receptors action in proliferative and differentiation capacities of NSCs. Aberrant expression or function of nuclear receptors in NSCs also contributes to the pathogenesis of various nervous system diseases. Here, we review recent advances in our understanding of the regulatory roles of steroid, non-steroid, and orphan nuclear receptors in NSC fate decisions. These studies establish nuclear receptors as key therapeutic targets in brain diseases.
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Affiliation(s)
- Dimitrios Gkikas
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Matina Tsampoula
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece
| | - Panagiotis K Politis
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str, 115 27, Athens, Greece.
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21
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O'Léime CS, Cryan JF, Nolan YM. Nuclear deterrents: Intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis. Brain Behav Immun 2017; 66:394-412. [PMID: 28751020 DOI: 10.1016/j.bbi.2017.07.153] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 07/15/2017] [Accepted: 07/23/2017] [Indexed: 12/11/2022] Open
Abstract
Hippocampal neurogenesis, the process by which new neurons are born and develop into the host circuitry, begins during embryonic development and persists throughout adulthood. Over the last decade considerable insights have been made into the role of hippocampal neurogenesis in cognitive function and the cellular mechanisms behind this process. Additionally, an increasing amount of evidence exists on the impact of environmental factors, such as stress and neuroinflammation on hippocampal neurogenesis and subsequent impairments in cognition. Elevated expression of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus is established as a significant contributor to the neuronal demise evident in many neurological and psychiatric disorders and is now known to negatively regulate hippocampal neurogenesis. In order to prevent the deleterious effects of IL-1β on neurogenesis it is necessary to identify signalling pathways and regulators of neurogenesis within neural progenitor cells that can interact with IL-1β. Nuclear receptors are ligand regulated transcription factors that are involved in modulating a large number of cellular processes including neurogenesis. In this review we focus on the signalling mechanisms of specific nuclear receptors involved in regulating neurogenesis (glucocorticoid receptors, peroxisome proliferator activated receptors, estrogen receptors, and nuclear receptor subfamily 2 group E member 1 (NR2E1 or TLX)). We propose that these nuclear receptors could be targeted to inhibit neuroinflammatory signalling pathways associated with IL-1β. We discuss their potential to be therapeutic targets for neuroinflammatory disorders affecting hippocampal neurogenesis and associated cognitive function.
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Affiliation(s)
- Ciarán S O'Léime
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland
| | - Yvonne M Nolan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland.
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22
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Maheu ME, Ressler KJ. Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders. Learn Mem 2017; 24:492-501. [PMID: 28814475 PMCID: PMC5580529 DOI: 10.1101/lm.044271.116] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 05/18/2017] [Indexed: 11/24/2022]
Abstract
The manipulation of neural plasticity as a means of intervening in the onset and progression of stress-related disorders retains its appeal for many researchers, despite our limited success in translating such interventions from the laboratory to the clinic. Given the challenges of identifying individual genetic variants that confer increased risk for illnesses like depression and post-traumatic stress disorder, some have turned their attention instead to focusing on so-called "master regulators" of plasticity that may provide a means of controlling these potentially impaired processes in psychiatric illnesses. The mammalian homolog of Tailless (TLX), Wnt, and the homeoprotein Otx2 have all been proposed to constitute master regulators of different forms of plasticity which have, in turn, each been implicated in learning and stress-related disorders. In the present review, we provide an overview of the changing distribution of these genes and their roles both during development and in the adult brain. We further discuss how their distinct expression profiles provide clues as to their function, and may inform their suitability as candidate drug targets in the treatment of psychiatric disorders.
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Affiliation(s)
- Marissa E Maheu
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA
| | - Kerry J Ressler
- Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA
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23
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Fulton J, Mazumder B, Whitchurch JB, Monteiro CJ, Collins HM, Chan CM, Clemente MP, Hernandez-Quiles M, Stewart EA, Amoaku WM, Moran PM, Mongan NP, Persson JL, Ali S, Heery DM. Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-γ (PPARγ) are disrupted by retinal disease-associated mutations. Cell Death Dis 2017; 8:e2677. [PMID: 28300834 PMCID: PMC5386588 DOI: 10.1038/cddis.2017.98] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 01/19/2017] [Accepted: 01/23/2017] [Indexed: 12/30/2022]
Abstract
Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-γ (PPARγ)/NR1C3 and thyroid hormone receptor b (TRb) TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARα/NR1C1 or PPARδ/NR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild-type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary, our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease.
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Affiliation(s)
- Joel Fulton
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Bismoy Mazumder
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | | | | | - Chun M Chan
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | | | - Elizabeth A Stewart
- Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK
| | - Winfried M Amoaku
- Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK
| | - Paula M Moran
- School of Psychology, University of Nottingham, Nottingham, UK
| | - Nigel P Mongan
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Jenny L Persson
- Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden
- Department of Molecular Biology, Umeå University, Umeå, Sweden
| | - Simak Ali
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - David M Heery
- School of Pharmacy, University of Nottingham, Nottingham, UK
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24
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Bodofsky S, Koitz F, Wightman B. CONSERVED AND EXAPTED FUNCTIONS OF NUCLEAR RECEPTORS IN ANIMAL DEVELOPMENT. NUCLEAR RECEPTOR RESEARCH 2017; 4:101305. [PMID: 29333434 PMCID: PMC5761748 DOI: 10.11131/2017/101305] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The nuclear receptor gene family includes 18 members that are broadly conserved among multiple disparate animal phyla, indicating that they trace their evolutionary origins to the time at which animal life arose. Typical nuclear receptors contain two major domains: a DNA-binding domain and a C-terminal domain that may bind a lipophilic hormone. Many of these nuclear receptors play varied roles in animal development, including coordination of life cycle events and cellular differentiation. The well-studied genetic model systems of Drosophila, C. elegans, and mouse permit an evaluation of the extent to which nuclear receptor function in development is conserved or exapted (repurposed) over animal evolution. While there are some specific examples of conserved functions and pathways, there are many clear examples of exaptation. Overall, the evolutionary theme of exaptation appears to be favored over strict functional conservation. Despite strong conservation of DNA-binding domain sequences and activity, the nuclear receptors prove to be highly-flexible regulators of animal development.
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Affiliation(s)
- Shari Bodofsky
- Biology Department, Muhlenberg College, 2400 Chew St., Allentown, PA 18104
| | - Francine Koitz
- Biology Department, Muhlenberg College, 2400 Chew St., Allentown, PA 18104
| | - Bruce Wightman
- Biology Department, Muhlenberg College, 2400 Chew St., Allentown, PA 18104
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25
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26
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Enhancer Analysis Unveils Genetic Interactions between TLX and SOX2 in Neural Stem Cells and In Vivo Reprogramming. Stem Cell Reports 2016; 5:805-815. [PMID: 26607952 PMCID: PMC4649261 DOI: 10.1016/j.stemcr.2015.09.015] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 09/16/2015] [Accepted: 09/17/2015] [Indexed: 12/26/2022] Open
Abstract
The orphan nuclear receptor TLX is a master regulator of postnatal neural stem cell (NSC) self-renewal and neurogenesis; however, it remains unclear how TLX expression is precisely regulated in these tissue-specific stem cells. Here, we show that a highly conserved cis-element within the Tlx locus functions to drive gene expression in NSCs. We demonstrate that the transcription factors SOX2 and MYT1 specifically interact with this genomic element to directly regulate Tlx enhancer activity in vivo. Knockdown experiments further reveal that SOX2 dominantly controls endogenous expression of TLX, whereas MYT1 only plays a modulatory role. Importantly, TLX is essential for SOX2-mediated in vivo reprogramming of astrocytes and itself is also sufficient to induce neurogenesis in the adult striatum. Together, these findings unveil functional genetic interactions among transcription factors that are critical to NSCs and in vivo cell reprogramming.
An evolutionarily conserved enhancer drives Tlx expression in neural stem cells SOX2 directly activates the identified enhancer and Tlx expression SOX2-mediated in vivo reprogramming of astrocytes to neuroblasts requires TLX
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Wu D, Cheung A, Wang Y, Yu S, Chan FL. The emerging roles of orphan nuclear receptors in prostate cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1866:23-36. [PMID: 27264242 DOI: 10.1016/j.bbcan.2016.06.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 05/31/2016] [Accepted: 06/01/2016] [Indexed: 12/25/2022]
Abstract
Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer.
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Affiliation(s)
- Dinglan Wu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Alyson Cheung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Yuliang Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Shan Yu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
| | - Franky L Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
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Olivares AM, Moreno-Ramos OA, Haider NB. Role of Nuclear Receptors in Central Nervous System Development and Associated Diseases. J Exp Neurosci 2016; 9:93-121. [PMID: 27168725 PMCID: PMC4859451 DOI: 10.4137/jen.s25480] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 01/06/2016] [Accepted: 01/07/2016] [Indexed: 11/13/2022] Open
Abstract
The nuclear hormone receptor (NHR) superfamily is composed of a wide range of receptors involved in a myriad of important biological processes, including development, growth, metabolism, and maintenance. Regulation of such wide variety of functions requires a complex system of gene regulation that includes interaction with transcription factors, chromatin-modifying complex, and the proper recognition of ligands. NHRs are able to coordinate the expression of genes in numerous pathways simultaneously. This review focuses on the role of nuclear receptors in the central nervous system and, in particular, their role in regulating the proper development and function of the brain and the eye. In addition, the review highlights the impact of mutations in NHRs on a spectrum of human diseases from autism to retinal degeneration.
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Affiliation(s)
- Ana Maria Olivares
- Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Oscar Andrés Moreno-Ramos
- Departamento de Ciencias Biológicas, Facultad de Ciencias, Universidad de los Andes, Bogotá, Colombia
| | - Neena B Haider
- Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
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29
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Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma. Exp Cell Res 2016; 343:118-125. [DOI: 10.1016/j.yexcr.2016.03.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 01/07/2023]
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The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. Nat Commun 2016; 7:10965. [PMID: 26965827 PMCID: PMC4793043 DOI: 10.1038/ncomms10965] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 02/05/2016] [Indexed: 01/03/2023] Open
Abstract
Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC-derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation. Dysregulation of microRNAs has been implicated in neurodevelopmental disorders, including schizophrenia. Here the authors show that the TLX-miR-219 cascade regulates the proliferation of neural stem cells during normal development, and this pathway is dysregulated in a schizophrenia iPSC model.
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31
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Davis SM, Thomas AL, Nomie KJ, Huang L, Dierick HA. Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis. Nat Commun 2016; 5:3177. [PMID: 24495972 DOI: 10.1038/ncomms4177] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 12/23/2013] [Indexed: 01/21/2023] Open
Abstract
Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour.
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Affiliation(s)
- Shaun M Davis
- 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA [2]
| | - Amanda L Thomas
- 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA [2]
| | - Krystle J Nomie
- 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA [2]
| | - Longwen Huang
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Herman A Dierick
- 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA [3] Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA [4] Program in Developmental Biology, Houston, Texas 77030, USA
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32
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Cui Q, Yang S, Ye P, Tian E, Sun G, Zhou J, Sun G, Liu X, Chen C, Murai K, Zhao C, Azizian KT, Yang L, Warden C, Wu X, D'Apuzzo M, Brown C, Badie B, Peng L, Riggs AD, Rossi JJ, Shi Y. Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis. Nat Commun 2016; 7:10637. [PMID: 26838672 PMCID: PMC4742843 DOI: 10.1038/ncomms10637] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/05/2016] [Indexed: 12/31/2022] Open
Abstract
Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma. TLX is a nuclear receptor essential for neural stem cell self-renewal and recently involved in glioblastoma development. In this study, the authors show that inhibition of TLX expression, achieved using a dendrimer nanovector-delivered siRNAs or viral vector-delivered shRNAs, reduces glioblastoma stem cells self renewal and in vivo tumour growth through activation of TET3.
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Affiliation(s)
- Qi Cui
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.,Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Su Yang
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.,Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Peng Ye
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - E Tian
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Guoqiang Sun
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Jiehua Zhou
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Guihua Sun
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Xiaoxuan Liu
- Aix-Marseille Université, CNRS, UMR 7325, Centre Interdisciplinaire de Nanoscience de Marseille, 13288 Marseille, France
| | - Chao Chen
- Aix-Marseille Université, CNRS, UMR 7325, Centre Interdisciplinaire de Nanoscience de Marseille, 13288 Marseille, France
| | - Kiyohito Murai
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Chunnian Zhao
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Krist T Azizian
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Lu Yang
- Integrative Genomics Core, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Charles Warden
- Integrative Genomics Core, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Xiwei Wu
- Integrative Genomics Core, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Massimo D'Apuzzo
- Department of Pathology, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Christine Brown
- Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Behnam Badie
- Department of Surgery, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Ling Peng
- Aix-Marseille Université, CNRS, UMR 7325, Centre Interdisciplinaire de Nanoscience de Marseille, 13288 Marseille, France
| | - Arthur D Riggs
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - John J Rossi
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.,Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
| | - Yanhong Shi
- Department of Developmental and Stem Cell Biology, Division of Stem Cell Biology Research, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.,Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA
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Wang T, Xiong JQ. The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases. Neurosci Bull 2016; 32:108-14. [PMID: 26769490 DOI: 10.1007/s12264-015-0004-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 09/26/2015] [Indexed: 12/24/2022] Open
Abstract
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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Affiliation(s)
- Tao Wang
- Department of Intensive Care, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China
| | - Jian-Qiong Xiong
- Department of Intensive Care, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
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34
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TLX-Its Emerging Role for Neurogenesis in Health and Disease. Mol Neurobiol 2016; 54:272-280. [PMID: 26738856 PMCID: PMC5219886 DOI: 10.1007/s12035-015-9608-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 12/03/2015] [Indexed: 02/07/2023]
Abstract
The orphan nuclear receptor TLX, also called NR2E1, is a factor important in the regulation of neural stem cell (NSC) self-renewal, neurogenesis, and maintenance. As a transcription factor, TLX is vital for the expression of genes implicated in neurogenesis, such as DNA replication, cell cycle, adhesion and migration. It acts by way of repressing or activating target genes, as well as controlling protein-protein interactions. Growing evidence suggests that dysregulated TLX acts in the initiation and progression of human disorders of the nervous system. This review describes recent knowledge about TLX expression, structure, targets, and biological functions, relevant to maintaining adult neural stem cells related to both neuropsychiatric conditions and certain nervous system tumours.
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35
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Nr2e1 Deficiency Augments Palmitate-Induced Oxidative Stress in Beta Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:9648769. [PMID: 26649147 PMCID: PMC4663339 DOI: 10.1155/2016/9648769] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 07/12/2015] [Accepted: 07/15/2015] [Indexed: 11/19/2022]
Abstract
Nuclear receptor subfamily 2 group E member 1 (Nr2e1) has been regarded as an essential regulator of the growth of neural stem cells. However, its function elsewhere is unknown. In the present study, we generated Nr2e1 knockdown MIN6 cells and studied whether Nr2e1 knockdown affected basal beta cell functions such as proliferation, cell death, and insulin secretion. We showed that knockdown of Nr2e1 in MIN6 cells resulted in increased sensitivity to lipotoxicity, decreased proliferation, a partial G0/G1 cell-cycle arrest, and higher rates of apoptosis. Moreover, Nr2e1 deficiency exaggerates palmitate-induced impairment in insulin secretion. At the molecular level, Nr2e1 deficiency augments palmitate-induced oxidative stress. Nr2e1 deficiency also resulted in decreases in antioxidant enzymes and expression level of Nrf2. Together, this study indicated a potential protective effect of Nr2e1 on beta cells, which may serve as a target for the development of novel therapies for diabetes.
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36
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Lüder CGK, Sumpf K, Nast R. Releasing the Brake on IFN-γ Signaling on Infection. Trends Parasitol 2015; 31:456-459. [PMID: 26422772 DOI: 10.1016/j.pt.2015.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 08/13/2015] [Indexed: 10/23/2022]
Abstract
Toxoplasma gondii effectively inhibits the responsiveness of its host cell to interferon gamma (IFN-γ). Using a genome-wide genetic screen, Beiting and colleagues have recently identified coactivators of the transcription factor STAT1 that can diminish this inhibitory effect. One of these coactivators, TLX, enhances type 1 helper (Th1) immune responses and restricts parasite replication during chronic toxoplasmosis.
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Affiliation(s)
- Carsten G K Lüder
- Institute for Medical Microbiology, Georg August University, Göttingen, Germany.
| | - Kristina Sumpf
- Institute for Medical Microbiology, Georg August University, Göttingen, Germany
| | - Roswitha Nast
- Institute for Medical Microbiology, Georg August University, Göttingen, Germany
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37
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Thomas AL, Davis SM, Dierick HA. Of Fighting Flies, Mice, and Men: Are Some of the Molecular and Neuronal Mechanisms of Aggression Universal in the Animal Kingdom? PLoS Genet 2015; 11:e1005416. [PMID: 26312756 PMCID: PMC4551476 DOI: 10.1371/journal.pgen.1005416] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Aggressive behavior is widespread in the animal kingdom, but the degree of molecular conservation between distantly related species is still unclear. Recent reports suggest that at least some of the molecular mechanisms underlying this complex behavior in flies show remarkable similarities with such mechanisms in mice and even humans. Surprisingly, some aspects of neuronal control of aggression also show remarkable similarity between these distantly related species. We will review these recent findings, address the evolutionary implications, and discuss the potential impact for our understanding of human diseases characterized by excessive aggression.
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Affiliation(s)
- Amanda L. Thomas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Shaun M. Davis
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Herman A. Dierick
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America
- * E-mail:
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38
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Cathcart P, Lucchesi W, Ottaviani S, De Giorgio A, Krell J, Stebbing J, Castellano L. Noncoding RNAs and the control of signalling via nuclear receptor regulation in health and disease. Best Pract Res Clin Endocrinol Metab 2015; 29:529-43. [PMID: 26303081 DOI: 10.1016/j.beem.2015.07.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Nuclear receptors belong to a superfamily of proteins that play central roles in human biology, orchestrating a large variety of biological functions in both health and disease. Understanding the interactions and regulatory pathways of NRs will allow development of potential therapeutic interventions for a multitude of disease processes. Non-coding RNAs have recently been discovered to have significant interactions with NR signalling pathways via a variety of biological connections. This review summarises the known interactions between ncRNAs and the NR superfamily in health, embryogenesis and a plethora of human diseases.
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Affiliation(s)
- Paul Cathcart
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London W12 0NN, UK
| | - Walter Lucchesi
- School of Pharmacy, University of Reading, Whiteknights Reading Berks RG6 6AP, UK
| | - Silvia Ottaviani
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London W12 0NN, UK
| | - Alex De Giorgio
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London W12 0NN, UK
| | - Jonathan Krell
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London W12 0NN, UK
| | - Justin Stebbing
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London W12 0NN, UK
| | - Leandro Castellano
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London W12 0NN, UK.
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Schmouth JF, Arenillas D, Corso-Díaz X, Xie YY, Bohacec S, Banks KG, Bonaguro RJ, Wong SH, Jones SJM, Marra MA, Simpson EM, Wasserman WW. Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development. BMC Genomics 2015. [PMID: 26204903 PMCID: PMC4512088 DOI: 10.1186/s12864-015-1770-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background Nr2e1 (nuclear receptor subfamily 2, group e, member 1) encodes a transcription factor important in neocortex development. Previous work has shown that nuclear receptors can have hundreds of target genes, and bind more than 300 co-interacting proteins. However, recognition of the critical role of Nr2e1 in neural stem cells and neocortex development is relatively recent, thus the molecular mechanisms involved for this nuclear receptor are only beginning to be understood. Serial analysis of gene expression (SAGE), has given researchers both qualitative and quantitative information pertaining to biological processes. Thus, in this work, six LongSAGE mouse libraries were generated from laser microdissected tissue samples of dorsal VZ/SVZ (ventricular zone and subventricular zone) from the telencephalon of wild-type (Wt) and Nr2e1-null embryos at the critical development ages E13.5, E15.5, and E17.5. We then used a novel approach, implementing multiple computational methods followed by biological validation to further our understanding of Nr2e1 in neocortex development. Results In this work, we have generated a list of 1279 genes that are differentially expressed in response to altered Nr2e1 expression during in vivo neocortex development. We have refined this list to 64 candidate direct-targets of NR2E1. Our data suggested distinct roles for Nr2e1 during different neocortex developmental stages. Most importantly, our results suggest a possible novel pathway by which Nr2e1 regulates neurogenesis, which includes Lhx2 as one of the candidate direct-target genes, and SOX9 as a co-interactor. Conclusions In conclusion, we have provided new candidate interacting partners and numerous well-developed testable hypotheses for understanding the pathways by which Nr2e1 functions to regulate neocortex development. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1770-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jean-François Schmouth
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. .,Genetics Graduate Program, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada. .,Current address: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, H3A 2B4, Canada.
| | - David Arenillas
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
| | - Ximena Corso-Díaz
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. .,Genetics Graduate Program, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada.
| | - Yuan-Yun Xie
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
| | - Slavita Bohacec
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
| | - Kathleen G Banks
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
| | - Russell J Bonaguro
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
| | - Siaw H Wong
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
| | - Steven J M Jones
- Genetics Graduate Program, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada. .,Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, V5Z 4S6, Canada. .,Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada. .,Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
| | - Marco A Marra
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, V5Z 4S6, Canada. .,Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
| | - Elizabeth M Simpson
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. .,Genetics Graduate Program, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada. .,Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. .,Department of Psychiatry, University of British Columbia, Vancouver, BC, V6T 2A1, Canada.
| | - Wyeth W Wasserman
- Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. .,Genetics Graduate Program, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada. .,Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
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40
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von Alpen D, Tran HV, Guex N, Venturini G, Munier FL, Schorderet DF, Haider NB, Escher P. Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain. Hum Mutat 2015; 36:599-610. [PMID: 25703721 DOI: 10.1002/humu.22775] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 02/10/2015] [Indexed: 11/11/2022]
Abstract
NR2E3 encodes the photoreceptor-specific nuclear hormone receptor that acts as a repressor of cone-specific gene expression in rod photoreceptors, and as an activator of several rod-specific genes. Recessive variants located in the ligand-binding domain (LBD) of NR2E3 cause enhanced short wavelength sensitive- (S-) cone syndrome (ESCS), a retinal degeneration characterized by an excess of S-cones and non-functional rods. We analyzed the dimerization properties of NR2E3 and the effect of disease-causing LBD missense variants by bioluminescence resonance energy transfer (BRET(2) ) protein interaction assays. Homodimerization was not affected in presence of p.A256V, p.R039G, p.R311Q, and p.R334G variants, but abolished in presence of p.L263P, p.L336P, p.L353V, p.R385P, and p.M407K variants. Homology modeling predicted structural changes induced by NR2E3 LBD variants. NR2E3 LBD variants did not affect interaction with CRX, but with NRL and rev-erbα/NR1D1. CRX and NRL heterodimerized more efficiently together, than did either with NR2E3. NR2E3 did not heterodimerize with TLX/NR2E1 and RXRα/NR2C1. The identification of a new compound heterozygous patient with detectable rod function, who expressed solely the p.A256V variant protein, suggests a correlation between LBD variants able to form functional NR2E3 dimers and atypical mild forms of ESCS with residual rod function.
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Affiliation(s)
- Désirée von Alpen
- IRO-Institute for Research in Ophthalmology, Sion, Switzerland.,EPFL-Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Hoai Viet Tran
- Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
| | - Nicolas Guex
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | - Francis L Munier
- Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
| | - Daniel F Schorderet
- IRO-Institute for Research in Ophthalmology, Sion, Switzerland.,EPFL-Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
| | - Neena B Haider
- Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute, Boston, Massachusetts
| | - Pascal Escher
- IRO-Institute for Research in Ophthalmology, Sion, Switzerland.,Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
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41
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Reinhardt R, Centanin L, Tavhelidse T, Inoue D, Wittbrodt B, Concordet JP, Martinez-Morales JR, Wittbrodt J. Sox2, Tlx, Gli3, and Her9 converge on Rx2 to define retinal stem cells in vivo. EMBO J 2015; 34:1572-88. [PMID: 25908840 PMCID: PMC4474531 DOI: 10.15252/embj.201490706] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 04/01/2015] [Indexed: 12/21/2022] Open
Abstract
Transcriptional networks defining stemness in adult neural stem cells (NSCs) are largely unknown. We used the proximal cis-regulatory element (pCRE) of the retina-specific homeobox gene 2 (rx2) to address such a network. Lineage analysis in the fish retina identified rx2 as marker for multipotent NSCs. rx2-positive cells located in the peripheral ciliary marginal zone behave as stem cells for the neuroretina, or the retinal pigmented epithelium. We identified upstream regulators of rx2 interrogating the rx2 pCRE in a trans-regulation screen and focused on four TFs (Sox2, Tlx, Gli3, and Her9) activating or repressing rx2 expression. We demonstrated direct interaction of the rx2 pCRE with the four factors in vitro and in vivo. By conditional mosaic gain- and loss-of-function analyses, we validated the activity of those factors on regulating rx2 transcription and consequently modulating neuroretinal and RPE stem cell features. This becomes obvious by the rx2-mutant phenotypes that together with the data presented above identify rx2 as a transcriptional hub balancing stemness of neuroretinal and RPE stem cells in the adult fish retina.
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Affiliation(s)
- Robert Reinhardt
- Centre for Organismal Studies (COS) Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Lázaro Centanin
- Centre for Organismal Studies (COS) Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Tinatini Tavhelidse
- Centre for Organismal Studies (COS) Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Daigo Inoue
- Centre for Organismal Studies (COS) Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Beate Wittbrodt
- Centre for Organismal Studies (COS) Heidelberg, Heidelberg University, Heidelberg, Germany
| | | | | | - Joachim Wittbrodt
- Centre for Organismal Studies (COS) Heidelberg, Heidelberg University, Heidelberg, Germany
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42
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Zhi X, Zhou XE, He Y, Searose-Xu K, Zhang CL, Tsai CC, Melcher K, Xu HE. Structural basis for corepressor assembly by the orphan nuclear receptor TLX. Genes Dev 2015; 29:440-50. [PMID: 25691470 PMCID: PMC4335298 DOI: 10.1101/gad.254904.114] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
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. Zhi et al. report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. Mutations that weaken the TLX–Atrophin interaction compromise the repressive activity of TLX. In addition, mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. 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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Affiliation(s)
- Xiaoyong Zhi
- Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA; Autophagy Research Center,
| | - X Edward Zhou
- Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
| | - Yuanzheng He
- Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
| | - Kelvin Searose-Xu
- Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
| | - Chun-Li Zhang
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Texas 75390, USA
| | - Chih-Cheng Tsai
- Department of Cell Biology and Neuroscience, University of California at Riverside, Riverside, California 92521, USA
| | - Karsten Melcher
- Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
| | - H Eric Xu
- Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA; Van Andel Research Institute-Shanghai Institute of Materia Medica (VARI/SIMM) Center, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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43
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Hartenstein V, Reh TA. Homologies between vertebrate and invertebrate eyes. Results Probl Cell Differ 2015; 37:219-55. [PMID: 25707078 DOI: 10.1007/978-3-540-45398-7_14] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Affiliation(s)
- Volker Hartenstein
- Department of Biology, University of California, Los Angeles, California, USA
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44
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Wu D, Yu S, Jia L, Zou C, Xu Z, Xiao L, Wong KB, Ng CF, Chan FL. Orphan nuclear receptor TLX functions as a potent suppressor of oncogene-induced senescence in prostate cancer via its transcriptional co-regulation of the CDKN1A
(p21WAF1
/
CIP1
) and SIRT1
genes. J Pathol 2015; 236:103-15. [DOI: 10.1002/path.4505] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 12/23/2014] [Accepted: 12/29/2014] [Indexed: 01/08/2023]
Affiliation(s)
- Dinglan Wu
- School of Biomedical Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Shan Yu
- School of Biomedical Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Lin Jia
- School of Biomedical Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Chang Zou
- School of Biomedical Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Zhenyu Xu
- School of Biomedical Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Lijia Xiao
- School of Biomedical Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Kam-Bo Wong
- School of Life Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Chi-Fai Ng
- Department of Surgery; Chinese University of Hong Kong, Hong Kong; People's Republic of China
| | - Franky L Chan
- School of Biomedical Sciences; Chinese University of Hong Kong, Hong Kong; People's Republic of China
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45
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Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee. Proc Natl Acad Sci U S A 2014; 111:17929-34. [PMID: 25453090 DOI: 10.1073/pnas.1420369111] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage-specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa.
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46
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Ni N, Zhang D, Xie Q, Chen J, Wang Z, Deng Y, Wen X, Zhu M, Ji J, Fan X, Luo M, Gu P. Effects of let-7b and TLX on the proliferation and differentiation of retinal progenitor cells in vitro. Sci Rep 2014; 4:6671. [PMID: 25327364 PMCID: PMC4202307 DOI: 10.1038/srep06671] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 08/21/2014] [Indexed: 02/03/2023] Open
Abstract
MicroRNAs manifest significant functions in brain neural stem cell (NSC) self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. Let-7b is expressed in the mammalian brain and regulates NSC proliferation and differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal. Whether let-7b and TLX act as important regulators in retinal progenitor cell (RPC) proliferation and differentiation remains unknown. Here, our data show that let-7b and TLX play important roles in controlling RPC fate determination in vitro. Let-7b suppresses TLX expression to negatively regulate RPC proliferation and accelerate the neuronal and glial differentiation of RPCs. The overexpression of let-7b downregulates TLX levels in RPCs, leading to reduced RPC proliferation and increased neuronal and glial differentiation, whereas antisense knockdown of let-7b produces robust TLX expression,enhanced RPC proliferation and decreased differentiation. Moreover, the inhibition of endogenous TLX by small interfering RNA suppresses RPC proliferation and promotes RPC differentiation. Furthermore, overexpression of TLX rescues let-7b-induced proliferation deficiency and weakens the RPC differentiation enhancement caused by let-7b alone. These results suggest that let-7b, by forming a negative feedback loop with TLX, provides a novel model to regulate the proliferation and differentiation of retinal progenitors in vitro.
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Affiliation(s)
- Ni Ni
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Dandan Zhang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Qing Xie
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Junzhao Chen
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Zi Wang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Yuan Deng
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Xuyang Wen
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Mengyu Zhu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Jing Ji
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Min Luo
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Ping Gu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
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Shimozaki K. Sox2 transcription network acts as a molecular switch to regulate properties of neural stem cells. World J Stem Cells 2014; 6:485-490. [PMID: 25258670 PMCID: PMC4172677 DOI: 10.4252/wjsc.v6.i4.485] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 08/29/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
Neural stem cells (NSCs) contribute to ontogeny by producing neurons at the appropriate time and location. Neurogenesis from NSCs is also involved in various biological functions in adults. Thus, NSCs continue to exert their effects throughout the lifespan of the organism. The mechanism regulating the core functional properties of NSCs is governed by intra- and extracellular signals. Among the transcription factors that serve as molecular switches, Sox2 is considered a key factor in NSCs. Sox2 forms a core network with partner factors, thereby functioning as a molecular switch. This review discusses how the network of Sox2 partner and target genes illustrates the molecular characteristics of the mechanism underlying the self-renewal and multipotency of NSCs.
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48
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Hu Y, Luo M, Ni N, Den Y, Xia J, Chen J, Ji J, Zhou X, Fan X, Gu P. Reciprocal actions of microRNA-9 and TLX in the proliferation and differentiation of retinal progenitor cells. Stem Cells Dev 2014; 23:2771-81. [PMID: 24901604 DOI: 10.1089/scd.2014.0021] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
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.
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Affiliation(s)
- Yamin Hu
- 1 Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai, China
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49
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The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable. PLoS One 2014; 9:e99440. [PMID: 24936658 PMCID: PMC4060991 DOI: 10.1371/journal.pone.0099440] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 05/14/2014] [Indexed: 12/31/2022] Open
Abstract
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.
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50
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Islam MM, Zhang CL. TLX: A master regulator for neural stem cell maintenance and neurogenesis. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:210-6. [PMID: 24930777 DOI: 10.1016/j.bbagrm.2014.06.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 04/22/2014] [Accepted: 06/05/2014] [Indexed: 10/25/2022]
Abstract
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.
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Affiliation(s)
- Mohammed M Islam
- Department of Molecular Biology, 6000 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Chun-Li Zhang
- Department of Molecular Biology, 6000 Harry Hines Blvd., Dallas, TX 75390, USA.
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