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 (<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^Y440X</i> mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that <i>SOX9^Y440X</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^Y440X/+</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^Y440X/+</i> 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 <i>Sox10</i>, 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.