Sox9; cochlea; development; differentiation; organ of Corti; Epithelium; Cell Differentiation; Electroporation; Hair Cells, Auditory; Cochlea; Biochemistry, Genetics and Molecular Biology (all); General Medicine
Abstract :
[en] 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.
Disciplines :
Human health sciences: Multidisciplinary, general & others
Huyghe, Aurélia ✱; Université de Liège - ULiège > Département des sciences cliniques > Neurologie
Van Den Ackerveken, Priscilla; Laboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liege, 4000 Liege, Belgium
Fukada, So-Ichiro ; Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
Kokubo, Hiroki; Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minamiku, Hiroshima 734-8551, Japan
Breuskin, Ingrid ; Université de Liège - ULiège > Centres attachés à la Faculté (Médecine) > GIGA - Neurosciences
Nguyen, Laurent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Delacroix, Laurence ✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Malgrange, Brigitte ✱; Université de Liège - ULiège > Département des sciences cliniques > Neurologie
✱ These authors have contributed equally to this work.
Language :
English
Title :
Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1.
Publication date :
25 August 2023
Journal title :
Cells
eISSN :
2073-4409
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Fonds Léon Fredericq [BE] FMRE - Fondation Médicale Reine Elisabeth [BE] BELSPO - Belgian Federal Science Policy Office [BE]
Funding text :
This research was funded by grants from the F.R.S.-F.N.R.S. (R.FNRS.4549), the Fonds Léon Frédéricq, the Fondation Médicale Reine Elisabeth and the Belgian Science Policy (IAP-VII network P7/7).
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