| First Author | Szeto IYY | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 46 | Pages | e2122121119 |
| PubMed ID | 36343245 | Mgi Jnum | J:332093 |
| Mgi Id | MGI:7408610 | Doi | 10.1073/pnas.2122121119 |
| Citation | Szeto IYY, et al. (2022) SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms. Proc Natl Acad Sci U S A 119(46):e2122121119 |
| abstractText | The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 (<i>SOX9</i>) and <i>SOX10</i> (<i>SOXE</i>) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia <i>SOX9<sup>Y440X</sup></i> mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that <i>SOX9<sup>Y440X</sup></i> causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous <i>Sox9</i>-null mice are normal. During the ES development of <i>Sox9<sup>Y440X/+</sup></i> heterozygotes, <i>Sox10</i> and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. <i>Sox10</i> heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early <i>Sox9<sup>Y440X/+</sup></i> mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9<sup>Y440X</sup> 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 <i>Sox10</i>, and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9<sup>Y440X</sup> 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 approximately 0.3% of newborns, and other syndromic disorders. |
