SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms.
SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms.
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DOI：
10.1073/pnas.2122121119
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发表时间：
2022-11-16
影响因子：
11.1
通讯作者：
Cheah, Kathryn S. E.
中科院分区：
文献类型：
--
作者：
Szeto, Irene Y. Y.;Chu, Daniel K. H.;Chen, Peikai;Chu, Ka Chi;Au, Tiffany Y. K.;Leung, Keith K. H.;Huang, Yong-Heng;Wynn, Sarah L.;Mak, Angel C. Y.;Chan, Ying-Shing;Chan, Wood Yee;Jauch, Ralf;Fritzsch, Bernd;Sham, Mai Har;Lovell-Badge, Robin;Cheah, Kathryn S. E.
关键词：
内淋巴系统受损是耳聋的常见原因。我们对Campomelic发育不良小鼠模型的研究揭示了SOX 9及其相关SOX 10在维持功能性内淋巴系统中的作用，Campomelic发育不良是一种以病因不明的耳聋为特征的综合征。在其发育的早期，这些SOXE因子对于调节祖细胞的分化以及离子转运蛋白和离子稳态所必需的通道的表达至关重要。随后，它们控制水/甘油通道Aqp 3的表达。这些数据为耳聋基因的发现提供了丰富的资源。由于SoxE基因在发育和干细胞中有许多作用，我们发现的原则可能适用于综合征的组织特异性效应。当SRY盒转录因子9（SOX 9）和SOX 10（SOXE）转录因子单独表达或共表达时，其突变引起显性综合征的体内机制尚不明确。我们建立了一个小鼠模型的campomelic发育不良SOX 9 Y 440 X突变，截短的反式激活结构域，但留下完整的DNA结合和二聚化。在这里，我们发现SOX 9 Y 440 X通过内淋巴囊（ES）/导管和耳蜗中的不同机制引起耳聋。相比之下，条件性杂合Sox 9缺失小鼠是正常的。在Sox 9 Y 440 X/+杂合子的ES发育过程中，Sox 10和对离子稳态重要的基因被下调，并且存在祖细胞的发育持续性，导致较少的成熟细胞。Sox 10杂合无效突变体也显示ES/导管祖细胞的持久性。相比之下，SOX 10在早期Sox 9 Y 440 X/+突变体耳蜗中保留了其表达。后来，在出生后的血管纹中，SOX 9 Y 440 X的显性干扰涉及损害SOX 9和SOX 10在抑制水通道水通道蛋白3表达中的正常合作，从而导致内淋巴水肿。我们的研究表明，对于内耳中功能正常的内淋巴系统，SOX 9调节Sox 10，并且根据细胞类型和靶基因，它独立于SOX 10或与SOX 10协同工作。SOX 9 Y 440 X可以干扰两种SOXE因子的活性，根据细胞/基因背景，其作用可以被分类为单倍不足/亚型或显性负性。这种转录因子伙伴关系破坏的模型可能适用于影响约0.3%新生儿的先天性耳聋和其他综合征性疾病。
Impairment of the endolymphatic system is a common cause of deafness. Our study of a mouse model of campomelic dysplasia, a syndrome characterized in part by deafness of unknown etiology, reveals the roles of SOX9 and its relative SOX10 in maintaining a functioning endolymphatic system. Early in its development, these SOXE factors are critical for regulating the differentiation of progenitors and the expression of ion transporters and channels essential for ionic homeostasis. Later, they control the expression of Aqp3, a water/glycerol channel. The data provide a rich resource for the discovery of deafness genes. Since SoxE genes have many roles in development and in stem cells, the principles we have found could be applicable to tissue-specific effects in syndromes. 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.
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影响因子：
3.3
作者：
Chizhikov VV;Iskusnykh IY;Fattakhov N;Fritzsch B
通讯作者：
Fritzsch B
DOI：
10.1083/jcb.201405098
发表时间：
2014-12-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bhattaram P;Penzo-Méndez A;Kato K;Bandyopadhyay K;Gadi A;Taketo MM;Lefebvre V
通讯作者：
Lefebvre V
影响因子：
16.2
作者：
Cowan, CA;Yokoyama, N;Fritzsch, B
通讯作者：
Fritzsch, B
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
3.6
作者：
Eckhard, Andreas;Gleiser, Corinna;Hirt, Bernhard
通讯作者：
Hirt, Bernhard