Androgne Recptor Gene Transcription in Sertoli Cells

摘要--项目2 主要调查者：特里·R·布朗 大量研究表明，雄激素受体(AR)及其配体，睾酮(T)， 是正常精子发生所必需的。最近发表的观察表明，患有Sertoli的小鼠 AR基因的细胞特异性条件性敲除不会产生精子提供了确凿的证据 在支持细胞中的表达是男性生育所必需的。然而，尽管 AR在调节精子发生中的作用，目前还没有全面的研究来了解AR是如何 表达本身是受调控的。这个应用的重点是定义分子和机制 在Sertoli细胞中驱动AR基因的表达。 大鼠、小鼠和人的支持细胞表现出高度一致的AR表达模式。在.期间 青春期成熟，当精子发生成为一个日益有效的过程时，有一个 支持细胞AR表达增加。成年后，支持细胞中AR的表达模式为 在周期的各个阶段与邻近生精细胞的进程同步 生精上皮。重要的是，AR表达水平最高的阶段 基因对雄激素的丢失刺激最为敏感。因此，这一点的中心假设 有观点认为，在青春期成熟和成年期间，支持细胞的AR的表达是 由一小部分转录因子及其同源顺式作用调节因子的活性决定 AR基因中的元素。在这些分子中，重要的是那些调节成熟的 AR基因转录的阶段性变化。这项提案的三个具体目标将受到考验 这一假说是通过确定转录因子和同源顺式作用调控元件在 大鼠AR基因启动子是AR成熟依赖和阶段特异性表达所必需的 Sertoli细胞，并通过以下方法确定这些元件和因子是否是体内表达AR所必需的 支持细胞。 人口控制以及生殖成功和失败仍然是公众面临的重大问题 健康。因此，我们提出的实验应该揭示调节AR的重要机制 不仅在啮齿类动物中表达，而且在人类中也表达，从而有助于我们对雄性的理解 生育能力。

ABSTRACT-PROJECT 2 Principal Investigator: Terry R. Brown Numerous studies have demonstrated that the androgen receptor (AR) and its ligand, testosterone (T), are required for normal spermatogenesis. Recently published observations showing that mice with Sertoli cell specific conditional knockout of the AR gene do not produce sperm provide definitive proof that AR expression in Sertoli cells is absolutely required for male fertility. However, despite the importance of the AR in the regulation of spermatogenesis, there has been no comprehensive effort to understand how AR expression itself is regulated. The focus of this application is to define the molecules and mechanisms that drive expression of the AR gene in Sertoli cells. Sertoli cells in rats, mice and men exhibit highly concordant patterns of AR expression. During pubertal maturation, when spermatogenesis becomes an increasingly efficient process, there is an increase in AR expression in Sertoli cells. In adulthood, the pattern of AR expression in Sertoli cells is synchronized with the progression of the neighboring spermatogenic cells through the stages of the cycle of the seminiferous epithelium. Importantly, the stages with the highest level of expression of the AR gene are the most sensitive to the loss of androgen stimulation. Thus, the central hypothesis of this proposal is that the expression of AR by Sertoli cells, both during pubertal maturation and in the adult, is determined by the activity of a small subset of transcription factors and their cognate cis-acting regulatory elements within the AR gene. Important among these molecules are those that regulate the maturational and stage-specific changes in AR gene transcription. The .three specific aims of this proposal will test this hypothesis by identifying the transcription factors and cognate cis-acting regulatory elements in the rat AR gene promoter that are required for maturation-dependent and stage-specific expression of AR by Sertoli cells and determine if those elements and factors are required for the in vivo expression of AR by Sertoli cells. Population control, as well as reproductive success and failure, remain significant issues for public health. Thus, our proposed experiments should reveal important mechanisms that regulate AR expression not only in rodents but also in humans, and thereby contribute to our understanding of male fertility.