Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells

During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has st...

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Authors: Rubbini, Davide, 1985-, Robert Moreno, Alexandre, Hoijman, Esteban, Alsina i Español, Berta
Format: article
Status:Published version
Publication Date:2015
Country:España
Institution:Universitat Pompeu Fabra
Repository:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/25428
Online Access:http://hdl.handle.net/10230/25428
http://dx.doi.org/10.1523/JNEUROSCI.1099-15.2015
Access Level:Open access
Keyword:Laberint (Orella) -- Anatomia
Peixos zebra
Hair cells
Inner ear
Lateral line
Regeneration
Retinoic acid
Zebrafish
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spelling Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cellsRubbini, Davide, 1985-Robert Moreno, AlexandreHoijman, EstebanAlsina i Español, BertaLaberint (Orella) -- AnatomiaPeixos zebraHair cellsInner earLateral lineRegenerationRetinoic acidZebrafishDuring development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown. Here, we use genetic and pharmacological inhibition to show that the RA pathway is required for hair cell regeneration in zebrafish. When regeneration is induced by laser ablation in the inner ear or by neomycin treatment in the lateral line, we observe rapid activation of several components of the RA pathway, with dynamics that position RA signaling upstream of other signaling pathways. We demonstrate that blockade of the RA pathway impairs cell proliferation of supporting cells in the inner ear and lateral line. Moreover, in neuromast, RA pathway regulates the transcription of p27(kip) and sox2 in supporting cells but not fgf3. Finally, genetic cell-lineage tracing using Kaede photoconversion demonstrates that de novo hair cells derive from FGF-active supporting cells. Our findings reveal that RA has a pivotal role in zebrafish hair cell regeneration by inducing supporting cell proliferation, and shed light on the underlying transcriptional mechanisms involved. This signaling pathway might be a promising approach for hearing recovery. SIGNIFICANCE STATEMENT: Hair cells are the specialized mechanosensory cells of the inner ear that capture auditory and balance sensory input. Hair cells die after acoustic trauma, ototoxic drugs or aging diseases, leading to progressive hearing loss. Mammals, in contrast to zebrafish, lack the ability to regenerate hair cells. Here, we find that retinoic acid (RA) pathway is required for hair cell regeneration in vivo in the zebrafish inner ear and lateral line. RA pathway is activated very early upon hair cell loss, promotes cell proliferation of progenitor cells, and regulates two key genes, p27(kip) and sox2. Our results position RA as an essential signal for hair cell regeneration with relevance in future regenerative strategies in mammals.This work was supported by Fundación Areces XVI CN Grants BFU2011-27006 and BFU2014-55738 REDT to B.A., A.R.-M. was supported by a Juan de la Cierva fellowship. D.R. holds an FI Generalitat de Cataluña fellowship. We thank the Advanced Light Microscopy Unit and A. Mallabiabarrena for helping with the laser ablation experiments; K. Poss and H. Roehl for providing the tg (hsp70:zdnRAR) and tg (hsp70:fgf3) transgenic lines, respectively; C. Cañestro for sharing unpublished data; and members of the laboratory for helpful discussions and suggestions.Society for Neuroscience201520162015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/25428http://dx.doi.org/10.1523/JNEUROSCI.1099-15.2015reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésJournal of neuroscience. 2015;35(47):15752-66© Society for Neuroscience http://www.jneurosci.org/content/35/47/15752.long The work is published under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/http://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/254282026-06-12T07:21:37Z
dc.title.none.fl_str_mv Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
title Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
spellingShingle Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
Rubbini, Davide, 1985-
Laberint (Orella) -- Anatomia
Peixos zebra
Hair cells
Inner ear
Lateral line
Regeneration
Retinoic acid
Zebrafish
title_short Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
title_full Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
title_fullStr Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
title_full_unstemmed Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
title_sort Retinoic acid signaling mediates hair cell regeneration by repressing p27kip and sox2 in supporting cells
dc.creator.none.fl_str_mv Rubbini, Davide, 1985-
Robert Moreno, Alexandre
Hoijman, Esteban
Alsina i Español, Berta
author Rubbini, Davide, 1985-
author_facet Rubbini, Davide, 1985-
Robert Moreno, Alexandre
Hoijman, Esteban
Alsina i Español, Berta
author_role author
author2 Robert Moreno, Alexandre
Hoijman, Esteban
Alsina i Español, Berta
author2_role author
author
author
dc.subject.none.fl_str_mv Laberint (Orella) -- Anatomia
Peixos zebra
Hair cells
Inner ear
Lateral line
Regeneration
Retinoic acid
Zebrafish
topic Laberint (Orella) -- Anatomia
Peixos zebra
Hair cells
Inner ear
Lateral line
Regeneration
Retinoic acid
Zebrafish
description During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown. Here, we use genetic and pharmacological inhibition to show that the RA pathway is required for hair cell regeneration in zebrafish. When regeneration is induced by laser ablation in the inner ear or by neomycin treatment in the lateral line, we observe rapid activation of several components of the RA pathway, with dynamics that position RA signaling upstream of other signaling pathways. We demonstrate that blockade of the RA pathway impairs cell proliferation of supporting cells in the inner ear and lateral line. Moreover, in neuromast, RA pathway regulates the transcription of p27(kip) and sox2 in supporting cells but not fgf3. Finally, genetic cell-lineage tracing using Kaede photoconversion demonstrates that de novo hair cells derive from FGF-active supporting cells. Our findings reveal that RA has a pivotal role in zebrafish hair cell regeneration by inducing supporting cell proliferation, and shed light on the underlying transcriptional mechanisms involved. This signaling pathway might be a promising approach for hearing recovery. SIGNIFICANCE STATEMENT: Hair cells are the specialized mechanosensory cells of the inner ear that capture auditory and balance sensory input. Hair cells die after acoustic trauma, ototoxic drugs or aging diseases, leading to progressive hearing loss. Mammals, in contrast to zebrafish, lack the ability to regenerate hair cells. Here, we find that retinoic acid (RA) pathway is required for hair cell regeneration in vivo in the zebrafish inner ear and lateral line. RA pathway is activated very early upon hair cell loss, promotes cell proliferation of progenitor cells, and regulates two key genes, p27(kip) and sox2. Our results position RA as an essential signal for hair cell regeneration with relevance in future regenerative strategies in mammals.
publishDate 2015
dc.date.none.fl_str_mv 2015
2015
2016
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/10230/25428
http://dx.doi.org/10.1523/JNEUROSCI.1099-15.2015
url http://hdl.handle.net/10230/25428
http://dx.doi.org/10.1523/JNEUROSCI.1099-15.2015
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Journal of neuroscience. 2015;35(47):15752-66
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
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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