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

发育为男性或女性的决定是由遗传途径控制的，该途径在人类胚胎中的睾丸或卵巢的发育中达到高潮。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，其中一些人在两个转录因子基因SRY和SOX 9中存在突变。SRY（Swyer综合征）或SOX 9（常染色体性反转-Campomelic发育不良）的突变导致具有男性染色体的个体发育为女性生殖结构。为了了解SRY和SOX 9如何决定性别，我们已经确定了四种与SRY和SOX 9相互作用的蛋白质。其中两种蛋白质，称为importin-beta和calmodulin，在将SRY和SOX 9转运到细胞核中发挥作用。另外两种蛋白质，称为PC 4和HSP 70，似乎参与与SRY和/或SOX 9的合作以打开基因。在发育中的小鼠睾丸中，大量基因在SRY和SOX 9表达后立即表达。我们将确定这50个基因中的哪些基因在性别决定过程中被SRY和SOX 9直接打开或关闭。这些研究将确定SRY和SOX 9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，我们希望确定新的基因参与性畸形综合征。

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.