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dc.contributor.authorRobert-Moreno, Alex-
dc.contributor.authorNaranjo, Silvia-
dc.contributor.authorCalle-Mustienes, Elisa de la-
dc.contributor.authorGómez-Skarmeta, José Luis-
dc.contributor.authorAlsina, Berta-
dc.date.accessioned2011-09-27T11:50:58Z-
dc.date.available2011-09-27T11:50:58Z-
dc.date.issued2010-12-31-
dc.identifier.citationPLoS ONE 5(12): e15907 (2010)es_ES
dc.identifier.otherPMC3013142-
dc.identifier.otherPMID: 21209840-
dc.identifier.urihttp://hdl.handle.net/10261/40113-
dc.description11 páginas, 7 figuras.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License.es_ES
dc.description.abstractPOU3F4 is a member of the POU-homedomain transcription factor family with a prominent role in inner ear development. Mutations in the human POU3F4 coding unit leads to X-linked deafness type 3 (DFN3), characterized by conductive hearing loss and progressive sensorineural deafness. Microdeletions found 1 Mb 5′ upstream of the coding region also displayed the same phenotype, suggesting that cis-regulatory elements might be present in that region. Indeed, we and others have recently identified several enhancers at the 1 Mb 5′ upstream interval of the pou3f4 locus. Here we characterize the spatio-temporal patterns of these regulatory elements in zebrafish transgenic lines. We show that the most distal enhancer (HCNR 81675) is activated earlier and drives GFP reporter expression initially to a broad ear domain to progressively restrict to the sensory patches. The proximal enhancer (HCNR 82478) is switched later during development and promotes expression, among in other tissues, in sensory patches from its onset. The third enhancer (HCNR 81728) is also active at later stages in the otic mesenchyme and in the otic epithelium. We also characterize the signaling pathways regulating these enhancers. While HCNR 81675 is regulated by very early signals of retinoic acid, HCNR 82478 is regulated by Fgf activity at a later stage and the HCNR 81728 enhancer is under the control of Hh signaling. Finally, we show that Sox2 and Pax2 transcription factors are bound to HCNR 81675 genomic region during otic development and specific mutations to these transcription factor binding sites abrogates HCNR 81675 enhancer activity. Altogether, our results suggest that pou3f4 expression in inner ear might be under the control of distinct regulatory elements that fine-tune the spatio-temporal activity of this gene and provides novel data on the signaling mechanisms controlling pou3f4 function.es_ES
dc.description.sponsorshipThis work has been supported by grants from MICINN to BA (BFU 2008-00714) and JLG-S (BFU2007-60042/BMC, Petri PET2007_0158, CSD2007-00008), a grant from the Junta de Andalucía to JLG-S (Proyecto de Excelencia CVI-3488) and a Juan de la Cierva postdoctoral fellowship to ARM.es_ES
dc.language.isoenges_ES
dc.publisherPublic Library of Sciencees_ES
dc.relation.isversionofPublisher’s version-
dc.rightsopenAccesses_ES
dc.subjectBinding Siteses_ES
dc.subjectEares_ES
dc.subjectEnharcer Elementses_ES
dc.subjectGene Deletiones_ES
dc.subjectGreen Fluorescent Proteinses_ES
dc.subjectMutationes_ES
dc.subjectPOU Domain Factorses_ES
dc.subjectTranscription factorses_ES
dc.subjectXenopuses_ES
dc.subjectZebrafishes_ES
dc.subjectPEOU3F4 proteines_ES
dc.titleCharacterization of New Otic Enhancers of the Pou3f4 Gene Reveal Distinct Signaling Pathway Regulation and Spatio-Temporal Patternses_ES
dc.typeartículoes_ES
dc.identifier.doi10.1371/journal.pone.0015907-
dc.description.peerreviewedPeer reviewedes_ES
dc.relation.publisherversionhttp://dx.doi.org/10.1371/journal.pone.0015907es_ES
dc.identifier.e-issn1932-6203-
dc.rights.licensehttp://creativecommons.org/licenses/by/4.0/-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderJunta de Andalucía-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004837es_ES
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