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Molecular mechanism of sex determination and its disease

性别决定及其疾病的分子机制

基本信息

批准号：
13670165
负责人：
SEMBA Kentaro
金额：
$ 2.18万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670165/
关键词：
sex SRY WT1 microarray DNA chip ゲノム

项目摘要

In humans, as in other mammals, sex determination is controlled by a dominant switch termed TDF for Testis Determining Factor. The SRY gene is thought to be the TDF, which encodes a transcription factor with one HMG box as a DNA binding domain. Mutations in the SRY HMG box have been identified in 15% cases of XY sex reversal in humans. Introduction of mouse SRY gene (Sry) into XX female mice induced testis differentiation and subsequent male development. However, little is known about mechanism of transcriptional regulation by SRY. Mutations of another transcription factor, WT1, are frequently observed in Denys-Drash syndrome (DDS) patients with urogenital malformation.During analysis of WT1-associated proteins, we found that WT1 bound to Sox30, which encodes a novel transcription factor with one HMG box. Further analysis showed that WT1 bound to its HMG box. This observation prompted us to analyze interaction between WT1 and SRY, both of which are expressed in the somatic cells of.early gonads. We published a paper describing the following results in Oncogene. i) WT1 binds to SRY in vitro and in cultured cells and this interaction is mediated by the zinc finger domain of WT1 and the HMG box of SRY. ii) WT1 and SRY synergistically activate transcription from a promoter that contains SRY binding sequence and also from the SRY promoter. WT1 mutants found in DDS, however, did not show this activity. iii) WT1 is recruited on a SRY-binding sequence in a SRY dependent manner, while recruitment of DDS mutants is significantly inhibited.These observations suggest that WT1 and SRY interaction plays an important role in early gonadal development and its disease.

与其他哺乳动物一样，人类的性别决定是由称为 TDF（睾丸决定因子）的显性开关控制的。 SRY基因被认为是TDF，它编码一种转录因子，具有一个HMG盒作为DNA结合域。在人类 15% 的 XY 性逆转病例中发现了 SRY HMG 盒的突变。将小鼠 SRY 基因 (Sry) 引入 XX 雌性小鼠中可诱导睾丸分化和随后的雄性发育。然而，人们对SRY的转录调控机制知之甚少。另一种转录因子 WT1 的突变在患有泌尿生殖畸形的 Denys-Drash 综合征 (DDS) 患者中经常观察到。在分析 WT1 相关蛋白时，我们发现 WT1 与 Sox30 结合，Sox30 编码一种带有一个 HMG 盒的新型转录因子。进一步分析表明WT1与其HMG盒结合。这一观察促使我们分析 WT1 和 SRY 之间的相互作用，这两者都在早期性腺的体细胞中表达。我们在 Oncogene 上发表了一篇论文，描述了以下结果。 i) WT1 在体外和培养细胞中与 SRY 结合，这种相互作用是由 WT1 的锌指结构域和 SRY 的 HMG 盒介导的。 ii) WT1和SRY协同激活包含SRY结合序列的启动子以及SRY启动子的转录。然而，DDS 中发现的 WT1 突变体并未表现出这种活性。 iii) WT1以SRY依赖性方式被招募到SRY结合序列上，而DDS突变体的招募被显着抑制。这些观察结果表明WT1和SRY相互作用在早期性腺发育及其疾病中发挥重要作用。