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

决定是作为男性还是女性发育是由一条遗传途径控制的，最终导致人类胚胎中的睾丸或卵巢的发育。这些生殖器官的正确发育依赖于转录因子对一系列基因的协调激活。对患有生殖器官缺陷的患者的分析表明，其中一些人在两个转录因子基因SRY和SOX9上存在突变。SRY(Swyer综合征)或SOX9(常染色体性反转-钟状发育不良)突变会导致具有男性染色体的个体中女性生殖结构的发育。为了了解SRY和SOX9是如何决定性别的，我们已经确定了四种与SRY和SOX9相互作用的蛋白质。其中两种蛋白质，称为输入素-β和钙调蛋白，在将SRY和SOX9运送到细胞核中起到了作用。另外两种蛋白质，称为PC4和HSP70，似乎参与了与SRY和-或SOX9的合作，以启动基因。在发育中的小鼠睾丸中，随着SRY和SOX9的表达，大量的基因同时表达。我们将确定在性别决定过程中，SRY和SOX9直接开启或关闭了这50个基因中的哪些。这些研究将确定SRY和SOX9如何引导正常的睾丸形成，以及突变如何导致发育缺陷。此外，通过解开睾丸形成途径，我们希望发现与性变形综合征相关的新基因。

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.