SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms

Irene Y Y Szeto; Daniel K H Chu; Peikai Chen; Ka Chi Chu; Tiffany Y K Au; Keith K H Leung; Yong-Heng Huang; Sarah L Wynn; Angel C Y Mak; Ying-Shing Chan; Wood Yee Chan; Ralf Jauch; Bernd Fritzsch; Mai Har Sham; Robin Lovell-Badge; Kathryn S E Cheah

doi:10.1073/pnas.2122121119

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SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms

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SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms

Irene Y Y Szeto, Daniel K H Chu, Peikai Chen, Ka Chi Chu, Tiffany Y K Au, Keith K H Leung, Yong-Heng Huang, Sarah L Wynn, Angel C Y Mak, Ying-Shing Chan, …

Proceedings of the National Academy of Sciences - PNAS, Vol.119(46), pp.e2122121119-e2122121119

11/16/2022

DOI: 10.1073/pnas.2122121119

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Abstract

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 SOX9Y440X mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9Y440X 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 Sox9Y440X/+ 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 Sox9Y440X/+ mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9Y440X 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. SOX9Y440X 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.

Details

Title: Subtitle: SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms
Creators: Irene Y Y Szeto - Li Ka Shing Faculty of Medicine, University of Hong Kong
Daniel K H Chu - Li Ka Shing Faculty of Medicine, University of Hong Kong
Peikai Chen - Li Ka Shing Faculty of Medicine, University of Hong Kong
Ka Chi Chu - Li Ka Shing Faculty of Medicine, University of Hong Kong
Tiffany Y K Au - Li Ka Shing Faculty of Medicine, University of Hong Kong
Keith K H Leung - Li Ka Shing Faculty of Medicine, University of Hong Kong
Yong-Heng Huang - Guangzhou Institutes of Biomedicine and Health
Sarah L Wynn - Li Ka Shing Faculty of Medicine, University of Hong Kong
Angel C Y Mak - University of Hong Kong
Ying-Shing Chan - Li Ka Shing Faculty of Medicine, University of Hong Kong
Wood Yee Chan - Chinese University of Hong Kong
Ralf Jauch - Li Ka Shing Faculty of Medicine, University of Hong Kong
Bernd Fritzsch - University of Iowa
Mai Har Sham - Li Ka Shing Faculty of Medicine, University of Hong Kong
Robin Lovell-Badge - The Francis Crick Institute
Kathryn S E Cheah - Li Ka Shing Faculty of Medicine, University of Hong Kong
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.119(46), pp.e2122121119-e2122121119
DOI: 10.1073/pnas.2122121119
eISSN: 1091-6490
Grant note: DOI: 10.13039/501100002920, name: Research Grants Council, University Grants Committee, award: HKU7222/97M; DOI: 10.13039/501100002920, name: Research Grants Council, University Grants Committee, award: HKU2/02C; DOI: 10.13039/501100002920, name: Research Grants Council, University Grants Committee, award: HKU4/05C; DOI: 10.13039/501100002920, name: Research Grants Council, University Grants Committee, award: AoE/M-04/04; DOI: 10.13039/501100002920, name: Research Grants Council, University Grants Committee, award: T12-708/12N; name: Jimmy and Emily Tang Professorship, award: Nil; DOI: 10.13039/100000072, name: HHS | NIH | National Institute of Dental and Craniofacial Research, award: R01 AG060504; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 31771454
Language: English
Date published: 11/16/2022
Academic Unit: Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984314167002771

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