Hdl Handle:
http://hdl.handle.net/10675.2/568
Title:
Estradiol Activates b-Catenin Dependent Transcription in Neurons
Authors:
Varea, Olga; Garrido, Juan Jose; Dopazo, Ana ( 0000-0002-4910-1684 ) ; Mendez, Pablo; Garcia-Segura, Luis Miguel; Wandosell, Francisco
Abstract:
Estradiol may fulfill a plethora of functions in neurons, in which much of its activity is associated with its capacity to directly bind and dimerize estrogen receptors. This hormone-protein complex can either bind directly to estrogen response elements (ERE's) in gene promoters, or it may act as a cofactor at non-ERE sites interacting with other DNA-binding elements such as AP-1 or c-Jun. Many of the neuroprotective effects described for estrogen have been associated with this mode of action. However, recent evidence suggests that in addition to these â genomic effectsâ , estrogen may also act as a more general â trophic factorâ triggering cytoplasmic signals and extending the potential activity of this hormone. We demonstrated that estrogen receptor alpha associates with b-catenin and glycogen synthase kinase 3 in the brain and in neurons, which has since been confirmed by others. Here, we show that the action of estradiol activates b-catenin transcription in neuroblastoma cells and in primary cortical neurons. This activation is time and concentration-dependent, and it may be abolished by the estrogen receptor antagonist ICI 182780. The transcriptional activation of b-catenin is dependent on lymphoid enhancer binding factor-1 (LEF-1) and a truncated-mutant of LEF-1 almost completely blocks estradiol TCF-mediated transcription. Transcription of a TCF-reporter in a transgenic mouse model is enhanced by estradiol in a similar fashion to that produced by Wnt3a. In addition, activation of a luciferase reporter driven by the engrailed promoter with three LEF-1 repeats was mediated by estradiol. We established a cell line that constitutively expresses a dominant-negative LEF-1 and it was used in a gene expression microarray analysis. In this way, genes that respond to estradiol or Wnt3a, sensitive to LEF-1, could be identified and validated. Together, these data demonstrate the existence of a new signaling pathway controlled by estradiol in neurons. This pathway shares some elements of the insulin-like growth factor-1/Insulin and Wnt signaling pathways, however, our data strongly suggest that it is different from that of both these ligands. These findings may reveal a set of new physiological roles for estrogens, at least in the Central Nervous System (CNS).
Editors:
Mei, Lin
Citation:
PLoS ONE. 2009 Apr 10; 4(4):e5153
Issue Date:
10-Apr-2009
URI:
http://hdl.handle.net/10675.2/568
DOI:
10.1371/journal.pone.0005153
PubMed ID:
19360103
PubMed Central ID:
PMC2664482
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorVarea, Olgaen_US
dc.contributor.authorGarrido, Juan Joseen_US
dc.contributor.authorDopazo, Anaen_US
dc.contributor.authorMendez, Pabloen_US
dc.contributor.authorGarcia-Segura, Luis Miguelen_US
dc.contributor.authorWandosell, Franciscoen_US
dc.contributor.editorMei, Lin-
dc.date.accessioned2012-10-26T16:26:43Z-
dc.date.available2012-10-26T16:26:43Z-
dc.date.issued2009-04-10en_US
dc.identifier.citationPLoS ONE. 2009 Apr 10; 4(4):e5153en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid19360103en_US
dc.identifier.doi10.1371/journal.pone.0005153en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/568-
dc.description.abstractEstradiol may fulfill a plethora of functions in neurons, in which much of its activity is associated with its capacity to directly bind and dimerize estrogen receptors. This hormone-protein complex can either bind directly to estrogen response elements (ERE's) in gene promoters, or it may act as a cofactor at non-ERE sites interacting with other DNA-binding elements such as AP-1 or c-Jun. Many of the neuroprotective effects described for estrogen have been associated with this mode of action. However, recent evidence suggests that in addition to these â genomic effectsâ , estrogen may also act as a more general â trophic factorâ triggering cytoplasmic signals and extending the potential activity of this hormone. We demonstrated that estrogen receptor alpha associates with b-catenin and glycogen synthase kinase 3 in the brain and in neurons, which has since been confirmed by others. Here, we show that the action of estradiol activates b-catenin transcription in neuroblastoma cells and in primary cortical neurons. This activation is time and concentration-dependent, and it may be abolished by the estrogen receptor antagonist ICI 182780. The transcriptional activation of b-catenin is dependent on lymphoid enhancer binding factor-1 (LEF-1) and a truncated-mutant of LEF-1 almost completely blocks estradiol TCF-mediated transcription. Transcription of a TCF-reporter in a transgenic mouse model is enhanced by estradiol in a similar fashion to that produced by Wnt3a. In addition, activation of a luciferase reporter driven by the engrailed promoter with three LEF-1 repeats was mediated by estradiol. We established a cell line that constitutively expresses a dominant-negative LEF-1 and it was used in a gene expression microarray analysis. In this way, genes that respond to estradiol or Wnt3a, sensitive to LEF-1, could be identified and validated. Together, these data demonstrate the existence of a new signaling pathway controlled by estradiol in neurons. This pathway shares some elements of the insulin-like growth factor-1/Insulin and Wnt signaling pathways, however, our data strongly suggest that it is different from that of both these ligands. These findings may reveal a set of new physiological roles for estrogens, at least in the Central Nervous System (CNS).en_US
dc.rightsVarea et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectNeuroscience/Neurodevelopmenten_US
dc.subjectNeuroscience/Neuronal Signaling Mechanismsen_US
dc.subjectDiabetes and Endocrinology/Endocrinologyen_US
dc.titleEstradiol Activates b-Catenin Dependent Transcription in Neuronsen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2664482en_US
dc.contributor.corporatenameDepartment of Neurology-
All Items in Scholarly Commons are protected by copyright, with all rights reserved, unless otherwise indicated.