Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1
It is widely accepted that cell fate determination in the cochlea is tightly controlled by different transcription factors (TFs) that remain to be fully defined. Here, we show that Sox9, initially expressed in the entire sensory epithelium of the cochlea, progressively disappears from differentiatin...
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MDPI AG
2023-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/17/2148 |
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| author | Mona Veithen Aurélia Huyghe Priscilla Van Den Ackerveken So-ichiro Fukada Hiroki Kokubo Ingrid Breuskin Laurent Nguyen Laurence Delacroix Brigitte Malgrange |
| author_facet | Mona Veithen Aurélia Huyghe Priscilla Van Den Ackerveken So-ichiro Fukada Hiroki Kokubo Ingrid Breuskin Laurent Nguyen Laurence Delacroix Brigitte Malgrange |
| author_sort | Mona Veithen |
| collection | DOAJ |
| description | It is widely accepted that cell fate determination in the cochlea is tightly controlled by different transcription factors (TFs) that remain to be fully defined. Here, we show that Sox9, initially expressed in the entire sensory epithelium of the cochlea, progressively disappears from differentiating hair cells (HCs) and is finally restricted to supporting cells (SCs). By performing ex vivo electroporation of E13.5–E14.5 cochleae, we demonstrate that maintenance of Sox9 expression in the progenitors committed to HC fate blocks their differentiation, even if co-expressed with Atoh1, a transcription factor necessary and sufficient to form HC. Sox9 inhibits Atoh1 transcriptional activity by upregulating Hey1 and HeyL antagonists, and genetic ablation of these genes induces extra HCs along the cochlea. Although Sox9 suppression from sensory progenitors ex vivo leads to a modest increase in the number of HCs, it is not sufficient in vivo to induce supernumerary HC production in an inducible Sox9 knockout model. Taken together, these data show that Sox9 is downregulated from nascent HCs to allow the unfolding of their differentiation program. This may be critical for future strategies to promote fully mature HC formation in regeneration approaches. |
| first_indexed | 2024-03-10T23:25:50Z |
| format | Article |
| id | doaj.art-833fa77d3c194997a6573af31ff1d261 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T23:25:50Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-833fa77d3c194997a6573af31ff1d2612023-11-19T07:57:54ZengMDPI AGCells2073-44092023-08-011217214810.3390/cells12172148Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1Mona Veithen0Aurélia Huyghe1Priscilla Van Den Ackerveken2So-ichiro Fukada3Hiroki Kokubo4Ingrid Breuskin5Laurent Nguyen6Laurence Delacroix7Brigitte Malgrange8Laboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liege, 4000 Liege, BelgiumLaboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liege, 4000 Liege, BelgiumLaboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liege, 4000 Liege, BelgiumLaboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, JapanGraduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minamiku, Hiroshima 734-8551, JapanLaboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liege, 4000 Liege, BelgiumLaboratory of Molecular Regulation of Neurogenesis, GIGA-Neurosciences, University of Liege, 4000 Liege, BelgiumLaboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liege, 4000 Liege, BelgiumLaboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liege, 4000 Liege, BelgiumIt is widely accepted that cell fate determination in the cochlea is tightly controlled by different transcription factors (TFs) that remain to be fully defined. Here, we show that Sox9, initially expressed in the entire sensory epithelium of the cochlea, progressively disappears from differentiating hair cells (HCs) and is finally restricted to supporting cells (SCs). By performing ex vivo electroporation of E13.5–E14.5 cochleae, we demonstrate that maintenance of Sox9 expression in the progenitors committed to HC fate blocks their differentiation, even if co-expressed with Atoh1, a transcription factor necessary and sufficient to form HC. Sox9 inhibits Atoh1 transcriptional activity by upregulating Hey1 and HeyL antagonists, and genetic ablation of these genes induces extra HCs along the cochlea. Although Sox9 suppression from sensory progenitors ex vivo leads to a modest increase in the number of HCs, it is not sufficient in vivo to induce supernumerary HC production in an inducible Sox9 knockout model. Taken together, these data show that Sox9 is downregulated from nascent HCs to allow the unfolding of their differentiation program. This may be critical for future strategies to promote fully mature HC formation in regeneration approaches.https://www.mdpi.com/2073-4409/12/17/2148Sox9cochleaorgan of Cortitransfectiondifferentiationdevelopment |
| spellingShingle | Mona Veithen Aurélia Huyghe Priscilla Van Den Ackerveken So-ichiro Fukada Hiroki Kokubo Ingrid Breuskin Laurent Nguyen Laurence Delacroix Brigitte Malgrange Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1 Cells Sox9 cochlea organ of Corti transfection differentiation development |
| title | Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1 |
| title_full | Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1 |
| title_fullStr | Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1 |
| title_full_unstemmed | Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1 |
| title_short | Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1 |
| title_sort | sox9 inhibits cochlear hair cell fate by upregulating hey1 and heyl antagonists of atoh1 |
| topic | Sox9 cochlea organ of Corti transfection differentiation development |
| url | https://www.mdpi.com/2073-4409/12/17/2148 |
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