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

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 fou...

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Autores: Robert Moreno, Alexandre, Naranjo, Silvia, de la Calle Mustienes, Elisa, Gómez Skarmeta, José Luis, Alsina i Español, Berta
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/23491
Acesso em linha:http://hdl.handle.net/10230/23491
http://dx.doi.org/10.1371/journal.pone.0015907
Access Level:acceso abierto
Palavra-chave:Laberint (Orella) -- Anatomia
Gens
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spelling Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patternsRobert Moreno, AlexandreNaranjo, Silviade la Calle Mustienes, ElisaGómez Skarmeta, José LuisAlsina i Español, BertaLaberint (Orella) -- AnatomiaGensPOU3F4 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.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 manuscriptPublic Library of Science (PLoS)201520152010info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/23491http://dx.doi.org/10.1371/journal.pone.0015907reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésPLoS ONE. 2010;5(12):e15907info:eu-repo/grantAgreement/ES/3PN/BFU2008-00714info:eu-repo/grantAgreement/ES/2PN/BFU2007-60042info:eu-repo/grantAgreement/ES/2PN/CSD2007-00008© 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 creditedinfo:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/234912026-06-12T07:21:37Z
dc.title.none.fl_str_mv Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
title Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
spellingShingle Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
Robert Moreno, Alexandre
Laberint (Orella) -- Anatomia
Gens
title_short Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
title_full Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
title_fullStr Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
title_full_unstemmed Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
title_sort Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns
dc.creator.none.fl_str_mv Robert Moreno, Alexandre
Naranjo, Silvia
de la Calle Mustienes, Elisa
Gómez Skarmeta, José Luis
Alsina i Español, Berta
author Robert Moreno, Alexandre
author_facet Robert Moreno, Alexandre
Naranjo, Silvia
de la Calle Mustienes, Elisa
Gómez Skarmeta, José Luis
Alsina i Español, Berta
author_role author
author2 Naranjo, Silvia
de la Calle Mustienes, Elisa
Gómez Skarmeta, José Luis
Alsina i Español, Berta
author2_role author
author
author
author
dc.subject.none.fl_str_mv Laberint (Orella) -- Anatomia
Gens
topic Laberint (Orella) -- Anatomia
Gens
description 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.
publishDate 2010
dc.date.none.fl_str_mv 2010
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/23491
http://dx.doi.org/10.1371/journal.pone.0015907
url http://hdl.handle.net/10230/23491
http://dx.doi.org/10.1371/journal.pone.0015907
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PLoS ONE. 2010;5(12):e15907
info:eu-repo/grantAgreement/ES/3PN/BFU2008-00714
info:eu-repo/grantAgreement/ES/2PN/BFU2007-60042
info:eu-repo/grantAgreement/ES/2PN/CSD2007-00008
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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