Sexually Dimorphic Regulation Of SF-1 In Gonadogenesis

SF-1 在性腺发生中的性二态性调节

• 批准号: 7000316
• 负责人: Joan S Jorgensen
• 金额: $ 18.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7000316
• 关键词: RNA interference; adrenal disorder; cell growth regulation; cell parasexuality; cell proliferation; gene expression; genetically modified animals; gonads; histogenesis; laboratory mouse; technology /technique development; testis; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Steroidogenic factor-1 (SF-1) plays pivotal roles in endocrine function and gonad development. Indeed, human patients with mutations in SF-1 are sex-reversed, lack normal gonad structure, and suffer from severe adrenal insufficiency. The SF-1 knock out mouse also has agenesis of gonads and adrenal glands. Sex-specific roles of SF-1 in gonad differentiation remain unknown because gonads in SF-1 disrupted animals are lost before the onset of sex determination. The main goal of this proposal is to identify the sex-specific functions of SF-1 during mouse gonad development. To examine the role of SF-1 during gonad development in both sexes, we have developed a technique to introduce nucleic acids into the urogenital ridge and monitor the ensuing consequences in culture. Our overall hypothesis is that the sexually dimorphic expression pattern of SF-1 is integral for male versus female gonadogenesis and is caused by sex-specific regulation of the SF-1 promoter. First, we will determine the consequences of SF-1 misexpression by targeting siRNAs specific for SF-1 in explant cultures of male gonads (Aim 1). Second, we will evaluate the 5' regulatory region of SF-1 in male and female gonad explant cultures to ascertain whether there are specific elements that target sex-specific expression of the gene (Aim 2). We have effectively eliminated the presence of SF-1 in siRNA treated gonads and have successfully targeted SF-1 promoter constructs to the correct cell types in males and females. These studies are the first known attempt to investigate the mechanism of SF-1 action in a live, intact, functioning gonad as it is developing. Findings resulting from these studies will have a profound impact on our current understanding of SF-1 function during gonad development. Furthermore, this method will enable scientists to embark on new studies on genes, known and unknown, that will lead to significant advances in the field of gonadogenesis and provide hope for a cure of gonadal anomalies including birth defects, infertility, and cancers.

描述（由申请人提供）：类固醇生成因子1（SF-1）在内分泌功能和性腺发育中扮演关键作用。实际上，SF-1突变的人类患者是性转化的，缺乏正常的性腺结构，并且患有严重的肾上腺功能不全。 SF-1敲除小鼠还具有性腺和肾上腺发育不全。 SF-1在性腺分化中的性别特异性作用仍然未知，因为在性别确定开始之前，SF-1中断动物的性腺损失了。该提案的主要目标是确定小鼠性腺发育过程中SF-1的性别特定功能。为了检查SF-1在性腺发育中的作用，我们已经开发了一种将核酸引入泌尿生殖器脊并监测培养物中随之而来的后果的技术。我们的总体假设是，SF-1的性二态表达模式对于雄性与女性染色体形成是不可或缺的，并且是由SF-1启动子的性别特异性调节引起的。首先，我们将通过针对雄性性腺外植体中SF-1特异性的siRNA来确定SF-1 Misexpress的后果（AIM 1）。其次，我们将评估男性和女性性腺外植体培养基中SF-1的5'调节区域，以确定是否存在针对基因性别表达的特定元素（AIM 2）。我们有效地消除了SF-1在经性性腺中的存在，并成功地将SF-1启动子构建体靶向了男性和女性的正确细胞类型。这些研究是研究SF-1作用机制在生存的性腺发育过程中的第一次已知尝试。这些研究产生的发现将对我们当前对性腺发展过程中SF-1功能的理解产生深远的影响。此外，这种方法将使科学家能够开始对已知和未知的基因研究，这将导致性腺发生领域取得重大进步，并为治愈性腺异常（包括孕源缺陷，不育，疾病和癌症）提供希望。