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Lef1-dependent hypothalamic neurogenesis inhibits anxiety.
Xie Y, Kaufmann D, Moulton MJ, Panahi S, Gaynes JA, Watters HN, Zhou D, Xue HH, Fung CM, Levine EM, Letsou A, Brennan KC, Dorsky RI
(2017) PLoS Biol 15: e2002257
MeSH Terms: Animals, Anxiety, Behavior, Animal, Biomarkers, Drosophila Proteins, Drosophila melanogaster, Female, Gene Expression Regulation, Genes, Reporter, Humans, Hypothalamus, Lymphoid Enhancer-Binding Factor 1, Male, Mice, Knockout, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Neurogenesis, Neurons, Species Specificity, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 14, 2018
While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/ß-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species.
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23 MeSH Terms
Smoking induces epithelial-to-mesenchymal transition in non-small cell lung cancer through HDAC-mediated downregulation of E-cadherin.
Nagathihalli NS, Massion PP, Gonzalez AL, Lu P, Datta PK
(2012) Mol Cancer Ther 11: 2362-72
MeSH Terms: Acetylation, Antigens, CD, Benzamides, Cadherins, Carcinoma, Non-Small-Cell Lung, Cell Movement, Down-Regulation, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Lung Neoplasms, Lymphoid Enhancer-Binding Factor 1, Neoplasm Invasiveness, Promoter Regions, Genetic, Pyridines, Smoking, Snail Family Transcription Factors, Survival Analysis, Transcription Factors, Transcription, Genetic
Show Abstract · Added June 14, 2013
Epidemiological studies have shown that most cases of lung cancers (85%-90%) are directly attributable to tobacco smoking. Although association between cigarette smoking and lung cancer is well documented, surprisingly little is known about the molecular mechanisms of how smoking is involved in epithelial-to-mesenchymal transition (EMT) through epigenetic changes. Here, we show that lung cancer patients with a smoking history have low E-cadherin levels and loss of E-cadherin is a poor prognostic factor in smokers. Moreover, the downregulation of E-cadherin correlates with the number of pack years. In an attempt to determine the role of long-term cigarette smoking on EMT, we observed that treatment of lung cell lines with cigarette smoke condensate (CSC) induces EMT through downregulation of epithelial markers, including E-cadherin and upregulation of mesenchymal markers. CSC decreases E-cadherin expression at the transcriptional level through upregulation of LEF1 and Slug, and knockdown of these two proteins increases E-cadherin expression. Importantly, chromatin immunoprecipitation assays suggest that LEF-1 and Slug binding to E-cadherin promoter is important for CSC-mediated downregulation of E-cadherin. The histone deacetylase (HDAC) inhibitor MS-275 reverses CSC-induced EMT, migration, and invasion through the restoration of E-cadherin expression. These results suggest that recruitment of HDACs by transcriptional repressors LEF-1 and Slug is responsible for E-cadherin suppression and EMT in cigarette smokers and provide a potential drug target toward the treatment of lung cancer.
©2012 AACR.
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2 Members
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23 MeSH Terms
Beta-catenin controls differentiation of the retinal pigment epithelium in the mouse optic cup by regulating Mitf and Otx2 expression.
Westenskow P, Piccolo S, Fuhrmann S
(2009) Development 136: 2505-10
MeSH Terms: Adherens Junctions, Animals, Binding Sites, Cell Adhesion, Cell Differentiation, Cell Transdifferentiation, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Lymphoid Enhancer-Binding Factor 1, Membrane Proteins, Mice, Microphthalmia-Associated Transcription Factor, Mutation, Neurons, Organ Specificity, Otx Transcription Factors, Protein Binding, Protein Transport, Retinal Pigment Epithelium, beta Catenin
Show Abstract · Added November 19, 2015
The retinal pigment epithelium (RPE) consists of a monolayer of cuboidal, pigmented cells that is located between the retina and the choroid. The RPE is vital for growth and function of the vertebrate eye and improper development results in congenital defects, such as microphthalmia or anophthalmia, or a change of cell fate into neural retina called transdifferentiation. The transcription factors microphthalmia-associated transcription factor (Mitf) and orthodenticle homolog 2 (Otx2) are crucial for RPE development and function; however, very little is known about their regulation. Here, by using a Wnt-responsive reporter, we show that the Wnt/beta-catenin pathway is activated in the differentiating mouse RPE. Cre-mediated, RPE-specific disruption of beta-catenin after the onset of RPE specification causes severe defects, resulting in microphthalmia with coloboma, disturbed lamination, and mislocalization of adherens junction proteins. Upon beta-catenin deletion, the RPE transforms into a multilayered tissue in which the expression of Mitf and Otx2 is downregulated, while retina-specific gene expression is induced, which results in the transdifferentiation of RPE into retina. Chromatin immunoprecipitation (ChIP) and luciferase assays indicate that beta-catenin binds near to and activates potential TCF/LEF sites in the Mitf and Otx2 enhancers. We conclude that Wnt/beta-catenin signaling is required for differentiation of the RPE by directly regulating the expression of Mitf and Otx2. Our study is the first to show that an extracellular signaling pathway directly regulates the expression of RPE-specific genes such as Mitf and Otx2, and elucidates a new role for the Wnt/beta-catenin pathway in organ formation and development.
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20 MeSH Terms
Tcf binding sequence and position determines beta-catenin and Lef-1 responsiveness of MMP-7 promoters.
Gustavson MD, Crawford HC, Fingleton B, Matrisian LM
(2004) Mol Carcinog 41: 125-39
MeSH Terms: Animals, Binding Sites, Cadherins, Cells, Cultured, Consensus Sequence, Cytoskeletal Proteins, DNA-Binding Proteins, Gene Expression Regulation, Humans, Kidney, Luciferases, Lymphoid Enhancer-Binding Factor 1, Matrix Metalloproteinase 7, Mice, Mice, Mutant Strains, Mutagenesis, Mutation, Promoter Regions, Genetic, Trans-Activators, Transcription Factors, Transcription Initiation Site, Transcription, Genetic, Transcriptional Activation, Transfection, beta Catenin
Show Abstract · Added March 5, 2014
The matrix metalloproteinase-7 (MMP-7) gene is a target of beta-catenin transactivation. Expression of the T-cell factor, Lef-1, enhances transcriptional activation of the human MMP-7 promoter by beta-catenin, but represses activation of the mouse MMP-7 promoter, both activities through consensus Tcf binding sites. The mouse promoter has a single Tcf binding element (mTBE) located downstream of the transcriptional start site, while the human promoter has two Tcf binding elements (hTBE1, hTBE2), both located upstream of the transcriptional start. hTBE1 and hTBE2 also differ in sequence from mTBE. Here we demonstrate that positioning of mTBE, upstream or downstream of the transcriptional start site dictated whether Lef-1 functioned as an activator or repressor, respectively. Sequence differences between mTBE and hTBE sites determined the potency of these activities, with hTBE sites being weaker. Mutational analysis of mTBE showed that increased Lef-1 activity mapped to G . C base pairings at 5' and 3' ends, and correlated with a threefold increase in Lef-1 binding affinity in vitro. Heterologous promoters with high affinity binding sites were 115-fold more responsive to beta-catenin than those with low affinity sites. Converting low affinity Tcf binding sites to high affinity sites increased beta-catenin responsiveness of the mouse and human promoters by 2-3 fold, and ectopic expression of Lef-1 increased beta-catenin responsiveness for promoters with low affinity binding sequences. We concluded that sequence and position of Tcf binding sites can determine the extent of beta-catenin-Lef-1 responsiveness for beta-catenin target genes.
1 Communities
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25 MeSH Terms
WNT signals are required for the initiation of hair follicle development.
Andl T, Reddy ST, Gaddapara T, Millar SE
(2002) Dev Cell 2: 643-53
MeSH Terms: Animals, Base Sequence, Cell Differentiation, Cell Division, Cytoskeletal Proteins, DNA-Binding Proteins, Edar Receptor, Epidermal Cells, Female, Gene Expression Regulation, Developmental, Hair, Hair Follicle, In Vitro Techniques, Intercellular Signaling Peptides and Proteins, Lymphoid Enhancer-Binding Factor 1, Mammary Glands, Animal, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Proteins, Proto-Oncogene Proteins, RNA, Messenger, Receptors, Ectodysplasin, Receptors, Tumor Necrosis Factor, Signal Transduction, Skin Physiological Phenomena, Tooth Abnormalities, Trans-Activators, Transcription Factors, Up-Regulation, Wnt Proteins, Zebrafish Proteins, beta Catenin
Show Abstract · Added January 30, 2013
Hair follicle morphogenesis is initiated by a dermal signal that induces the development of placodes in the overlying epithelium. To determine whether WNT signals are required for initiation of follicular development, we ectopically expressed Dickkopf 1, a potent diffusible inhibitor of WNT action, in the skin of transgenic mice. This produced a complete failure of placode formation prior to morphological or molecular signs of differentiation, and blocked tooth and mammary gland development before the bud stage. This phenotype indicates that activation of WNT signaling in the skin precedes, and is required for, localized expression of regulatory genes and initiation of hair follicle placode formation.
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35 MeSH Terms
The PEA3 subfamily of Ets transcription factors synergizes with beta-catenin-LEF-1 to activate matrilysin transcription in intestinal tumors.
Crawford HC, Fingleton B, Gustavson MD, Kurpios N, Wagenaar RA, Hassell JA, Matrisian LM
(2001) Mol Cell Biol 21: 1370-83
MeSH Terms: Animals, Base Sequence, Binding Sites, Colonic Neoplasms, Cytoskeletal Proteins, DNA Primers, DNA-Binding Proteins, Genes, Reporter, Humans, Intestinal Neoplasms, Luciferases, Lymphoid Enhancer-Binding Factor 1, Matrix Metalloproteinase 7, Mice, Mutagenesis, Site-Directed, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun, Trans-Activators, Transcription Factors, Transcriptional Activation, Tumor Cells, Cultured, beta Catenin
Show Abstract · Added March 5, 2014
The matrix metalloproteinase matrilysin (MMP-7) is expressed in the tumor cells of a majority of mouse intestinal and human colonic adenomas. We showed previously that matrilysin is a target gene of beta-catenin-Tcf, the transcription factor complex whose activity is thought to play a crucial role in the initiation of intestinal tumorigenesis. Here we report that overexpression of a stable mutant form of beta-catenin alone was not sufficient to effect expression of luciferase from a matrilysin promoter-luciferase reporter plasmid. However, cotransfection of the reporter with an expression vector encoding the PEA3 Ets transcription factor, or its close relatives ER81 and ERM, increased luciferase expression and rendered the promoter responsive to beta-catenin-LEF-1 as well as to the AP-1 protein c-Jun. Other Ets proteins could not substitute for the PEA3 subfamily. Luciferase activity was induced up to 250-fold when PEA3, c-Jun, beta-catenin, and LEF-1 were coexpressed. This combination of transcription factors was also sufficient to induce expression of the endogenous matrilysin gene. Furthermore, all matrilysin-expressing benign intestinal tumors of the Min mouse expressed a member of the PEA3 subfamily, as did all human colon tumor cell lines examined. These data suggest that the expression of members of the PEA3 subfamily, in conjunction with the accumulation of beta-catenin in these tumors, leads to coordinate upregulation of matrilysin gene transcription, contributing to gastrointestinal tumorigenesis.
1 Communities
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22 MeSH Terms
The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors.
Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM
(1999) Oncogene 18: 2883-91
MeSH Terms: Adenoma, Animals, Base Sequence, Cytoskeletal Proteins, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Intestinal Neoplasms, Lymphoid Enhancer-Binding Factor 1, Matrix Metalloproteinase 7, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Promoter Regions, Genetic, Signal Transduction, Trans-Activators, Transcription Factors, Transcriptional Activation, beta Catenin
Show Abstract · Added March 5, 2014
Matrilysin is a matrix metalloproteinase expressed in the tumor cells of greater than 80% of intestinal adenomas. The majority of these intestinal tumors are associated with the accumulation of beta-catenin, a component of the cadherin adhesion complex and, through its association with the T Cell Factor (Tcf) DNA binding proteins, a regulator in the Wnt signal transduction pathway. In murine intestinal tumors, matrilysin transcripts show striking overlap with the accumulation of beta-catenin protein. The matrilysin promoter is upregulated as much as 12-fold by beta-catenin in colon tumor cell lines in a manner inversely proportional to the endogenous levels of beta-catenin/Tcf complex and is dependent upon a single optimal Tcf-4 recognition site. Coexpression of the E-cadherin cytoplasmic domain blocked this induction and reduced basal promoter activity in every colon cancer cell line tested. Inactivation of the Tcf binding site increased promoter activity and overexpression of the Tcf factor, LEF-1, significantly downregulated matrilysin promoter activity, suggesting that beta-catenin transactivates the matrilysin promoter by virtue of its ability to abrogate Tcf-mediated repression. Because genetic ablation of matrilysin decreases tumor formation in multiple intestinal neoplasia (Min) mice, we propose that regulation of matrilysin production by beta-catenin accumulation is a contributing factor to intestinal tumorigenesis.
1 Communities
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19 MeSH Terms