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SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms
The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 (SOX9) and SOX10 (SOXE) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9(Y440X) mutati...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674217/ https://www.ncbi.nlm.nih.gov/pubmed/36343245 http://dx.doi.org/10.1073/pnas.2122121119 |
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author | Szeto, Irene Y. Y. Chu, Daniel K. H. Chen, Peikai Chu, Ka Chi Au, Tiffany Y. K. Leung, Keith K. H. Huang, Yong-Heng Wynn, Sarah L. Mak, Angel C. Y. Chan, Ying-Shing Chan, Wood Yee Jauch, Ralf Fritzsch, Bernd Sham, Mai Har Lovell-Badge, Robin Cheah, Kathryn S. E. |
author_facet | Szeto, Irene Y. Y. Chu, Daniel K. H. Chen, Peikai Chu, Ka Chi Au, Tiffany Y. K. Leung, Keith K. H. Huang, Yong-Heng Wynn, Sarah L. Mak, Angel C. Y. Chan, Ying-Shing Chan, Wood Yee Jauch, Ralf Fritzsch, Bernd Sham, Mai Har Lovell-Badge, Robin Cheah, Kathryn S. E. |
author_sort | Szeto, Irene Y. Y. |
collection | PubMed |
description | The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 (SOX9) and SOX10 (SOXE) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9(Y440X) mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9(Y440X) causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous Sox9-null mice are normal. During the ES development of Sox9(Y440X/+) heterozygotes, Sox10 and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. Sox10 heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early Sox9(Y440X/+) mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9(Y440X) is implicated in impairing the normal cooperation of SOX9 and SOX10 in repressing the expression of the water channel Aquaporin 3, thereby contributing to endolymphatic hydrops. Our study shows that for a functioning endolymphatic system in the inner ear, SOX9 regulates Sox10, and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9(Y440X) can interfere with the activity of both SOXE factors, exerting effects that can be classified as haploinsufficient/hypomorphic or dominant negative depending on the cell/gene context. This model of disruption of transcription factor partnerships may be applicable to congenital deafness, which affects ∼0.3% of newborns, and other syndromic disorders. |
format | Online Article Text |
id | pubmed-9674217 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-96742172023-05-07 SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms Szeto, Irene Y. Y. Chu, Daniel K. H. Chen, Peikai Chu, Ka Chi Au, Tiffany Y. K. Leung, Keith K. H. Huang, Yong-Heng Wynn, Sarah L. Mak, Angel C. Y. Chan, Ying-Shing Chan, Wood Yee Jauch, Ralf Fritzsch, Bernd Sham, Mai Har Lovell-Badge, Robin Cheah, Kathryn S. E. Proc Natl Acad Sci U S A Biological Sciences The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 (SOX9) and SOX10 (SOXE) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9(Y440X) mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9(Y440X) causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous Sox9-null mice are normal. During the ES development of Sox9(Y440X/+) heterozygotes, Sox10 and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. Sox10 heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early Sox9(Y440X/+) mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9(Y440X) is implicated in impairing the normal cooperation of SOX9 and SOX10 in repressing the expression of the water channel Aquaporin 3, thereby contributing to endolymphatic hydrops. Our study shows that for a functioning endolymphatic system in the inner ear, SOX9 regulates Sox10, and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9(Y440X) can interfere with the activity of both SOXE factors, exerting effects that can be classified as haploinsufficient/hypomorphic or dominant negative depending on the cell/gene context. This model of disruption of transcription factor partnerships may be applicable to congenital deafness, which affects ∼0.3% of newborns, and other syndromic disorders. National Academy of Sciences 2022-11-07 2022-11-15 /pmc/articles/PMC9674217/ /pubmed/36343245 http://dx.doi.org/10.1073/pnas.2122121119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Szeto, Irene Y. Y. Chu, Daniel K. H. Chen, Peikai Chu, Ka Chi Au, Tiffany Y. K. Leung, Keith K. H. Huang, Yong-Heng Wynn, Sarah L. Mak, Angel C. Y. Chan, Ying-Shing Chan, Wood Yee Jauch, Ralf Fritzsch, Bernd Sham, Mai Har Lovell-Badge, Robin Cheah, Kathryn S. E. SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms |
title | SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms |
title_full | SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms |
title_fullStr | SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms |
title_full_unstemmed | SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms |
title_short | SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms |
title_sort | sox9 and sox10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674217/ https://www.ncbi.nlm.nih.gov/pubmed/36343245 http://dx.doi.org/10.1073/pnas.2122121119 |
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