PDF(Pubmed)
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.
摘要：
由SRY盒转录因子9（SOX9）和SOX10（SOXE）转录因子突变引起的显性综合征的体内机制，当它们单独表达或共同表达时，是不明确的。我们创建了一个小鼠模型，用于研究高峰发育不良SOX9Y440X突变，其截短反式激活结构域但留下DNA结合和二聚化完整。这里,我们发现SOX9Y440X通过内淋巴囊（ES）/导管和耳蜗的不同机制引起耳聋。相比之下,条件性杂合Sox9-null小鼠是正常的。在Sox9Y440X/+杂合子的ES发育过程中，Sox10和对离子稳态重要的基因被下调，祖细胞的发育持久性，导致成熟细胞减少。Sox10杂合无效突变体也显示出ES/导管祖细胞的持久性。相比之下,SOX10在早期Sox9Y440X/+突变耳蜗中保留其表达。稍后，在产后血管纹中，SOX9Y440X的主要干扰涉及损害SOX9和SOX10在抑制水通道水通道蛋白3表达中的正常合作，从而导致内淋巴积水。我们的研究表明，对于内耳内淋巴系统的功能，SOX9调节Sox10，并根据细胞类型和靶基因，它独立于SOX10或与SOX10合作工作。SOX9Y440X可以干扰两种SOXE因子的活性，根据细胞/基因背景，发挥可分为单倍体不足/低态或显性阴性的作用。这种转录因子伙伴关系破坏的模型可能适用于先天性耳聋，这影响了0.3%的新生儿，和其他综合症。
