Interaction among SOX10 PAX3 and MITF, three genes altered in Waardenburg syndrome
Interaction among SOX10 PAX3 and MITF, three genes altered in Waardenburg syndrome
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DOI：
10.1093/hmg/9.13.1907
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发表时间：
2000-08-12
影响因子：
3.5
通讯作者：
Goossens, M
中科院分区：
文献类型：
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作者：
Bondurand, N;Pingault, V;Goossens, M
Waardenburg综合征（WS）是一种常染色体显性遗传疾病，发病率为1/40 000，表现为感音神经性耳聋和色素沉着缺陷。根据是否存在其他症状，将其分为四种类型。WS 1和WS 3是由于PAX 3基因的突变，而一些WS 2病例与小眼症相关转录因子（MITF）基因的突变有关。WS 4表型可由内皮素-B受体基因（EDNRB）、其配体内皮素-3（EDN 3）基因或SOX 10基因突变引起。PAX 3已经显示出调节MITF基因表达。最近的SOX 10在WS 4中的作用促使我们测试这种已知在体外与PAX 3合作的转录因子是否也能够调节MITF启动子的表达。在这里，我们表明，SOX 10，与PAX 3的协同作用，强烈激活MITF的表达在转染试验。分析表明，PAX 3和SOX 10直接相互作用的MITF启动子的近端区域包含两个因子的结合位点的结合。此外，S 0X 10或PAX 3突变蛋白不能反式激活该启动子，提供了这两个基因协同作用以直接调节MITF的表达的进一步证据。在显性巨结肠（Dom）小鼠中进行的原位杂交实验证实，S 0X 10功能障碍损害MITF表达以及黑素细胞发育和存活。这些实验证明了在WS中改变的三个基因之间的相互作用，可以解释这种疾病的腹泻症状。
Waardenburg syndrome (WS) is an autosomal dominant disorder with an incidence of 1 in 40 000 that manifests with sensorineural deafness and pigmentation defects. It is classified into four types depending on the presence or absence of additional symptoms. WS1 and WS3 are due to mutations in the PAX3 gene whereas some WS2 cases are associated with mutations in the microphthalmia-associated transcription factor (MITF) gene. The WS4 phenotype can result from mutations in the endothelin-B receptor gene (EDNRB), in the gene for its ligand, endothelin-3 (EDN3), or in the SOX10 gene. PAX3 has been shown to regulate MITF gene expression. The recent implication of SOX10 in WS4 prompted us to test whether this transcription factor, known to cooperate in vitro with PAX3, is also able to regulate expression from the MITF promoter. Here we show that SOX10, in synergy with PAX3, strongly activates MITF expression in transfection assays. Analyses revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Moreover, SOX10 or PAX3 mutant proteins fail to transactivate this promoter, providing further evidence that the two genes act in concert to directly regulate expression of MITF, In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse, confirmed that SOX10 dysfunction impairs Mitf expression as well as melanocytic development and survival. These experiments, which demonstrate an interaction between three of the genes that are altered in WS, could explain the auditory-pigmentary symptoms of this disease.