Role of human SRY and SOX9 in sex determination and disease.

人类 SRY 和 SOX9 在性别决定和疾病中的作用。

• 批准号: nhmrc : 198713
• 负责人: Prof Vincent Harley
• 金额: $ 20.59万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2002
• 资助国家: 澳大利亚
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-human-sry-determination-disease/96134
• 关键词: Role; human; SRY; SOX9; sex

The decision to develop as a male or female is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. The correct development of these reproductive organs depends on the coordinated activation of a network of genes by transcription factors. Analysis of patients with defective reproductive organs has shown that a number of these individuals have mutations in two transcription factor genes, SRY and SOX9. Mutations in SRY (Swyer syndrome) or SOX9 (autosomal sex reversal-campomelic dysplasia) cause the development of female reproductive structures in individuals with male chromosomes. Towards understanding how SRY and SOX9 work to determine sex, we have identified four proteins that interact with SRY and SOX9. Two of these proteins, called importin-beta and calmodulin have a role in transporting SRY and SOX9 into the cell nucleus. The other two proteins, called PC4 and HSP70, appear to be involved in co-operating with SRY and-or SOX9 to turn genes on. In the developing mouse testis, a large number of genes are expressed at the time immediately following the expression of SRY and SOX9. We will identify which of these 50 genes are being directly switched on or off by SRY and SOX9 during sex determination. These studies will identify how SRY and SOX9 direct normal testis formation and how mutations cause developmental defects. Also, by unravelling the testis formation pathway, we expect to identify new genes involved in sexual dysmorphology syndromes.

发育为男性或女性的决定是由一种遗传途径控制的，这种遗传途径在人类胚胎中睾丸或卵巢的发育中达到顶峰。这些生殖器官的正确发育取决于转录因子对基因网络的协调激活。对生殖器官缺陷患者的分析表明，这些患者中的许多人在两种转录因子基因SRY和SOX9中发生突变。SRY （Swyer综合征）或SOX9（常染色体性反转-同源性发育不良）的突变导致男性染色体个体的女性生殖结构发育。为了了解SRY和SOX9如何决定性别，我们已经确定了四种与SRY和SOX9相互作用的蛋白质。其中两种蛋白，叫做进口蛋白- β和钙调蛋白，在将SRY和SOX9转运到细胞核中起作用。另外两种蛋白质，PC4和HSP70，似乎参与了与SRY和或SOX9的合作，从而开启基因。在发育中的小鼠睾丸中，大量基因在SRY和SOX9表达之后立即表达。我们将确定在性别决定过程中，SRY和SOX9直接开启或关闭这50个基因中的哪些。这些研究将确定SRY和SOX9如何指导正常睾丸的形成以及突变如何导致发育缺陷。此外，通过解开睾丸形成途径，我们期望识别涉及性畸形综合征的新基因。