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Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns

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dc.contributor.author Robert Moreno, Alexandre
dc.contributor.author Naranjo, Silvia
dc.contributor.author de la Calle Mustienes, Elisa
dc.contributor.author Gómez Skarmeta, José Luis
dc.contributor.author Alsina i Español, Berta
dc.date.accessioned 2015-04-29T09:17:08Z
dc.date.available 2015-04-29T09:17:08Z
dc.date.issued 2010
dc.identifier.citation Robert-Moreno A, Naranjo S, de la Calle-Mustienes E, Gomez-Skarmeta JL, Alsina B. Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns. PLoS ONE. 2010;5(12):e15907. DOI: 10.1371/journal.pone.0015907
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10230/23491
dc.description.abstract POU3F4 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.
dc.description.sponsorship This 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartof PLoS ONE. 2010;5(12):e15907
dc.rights © 2010 Robert-Moreno 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
dc.subject.other Laberint (Orella) -- Anatomia
dc.subject.other Gens
dc.title Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0015907
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2008-00714
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/BFU2007-60042
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/CSD2007-00008
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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