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: 6861432
• 负责人: Joan S Jorgensen
• 金额: $ 22万
• 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 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861432
• 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.

性状（由申请方提供）：类固醇生成因子-1（SF-1）在内分泌功能和性腺发育中起关键作用。事实上，SF-1突变的人类患者是性别颠倒的，缺乏正常的性腺结构，并患有严重的肾上腺功能不全。SF-1基因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SF-1破坏的动物的性腺在性别决定开始之前丢失。该提案的主要目标是确定SF-1在小鼠性腺发育过程中的性别特异性功能。为了研究SF-1在两性性腺发育过程中的作用，我们开发了一种技术，将核酸引入泌尿生殖嵴，并在培养中监测随后的后果。我们的总体假设是，SF-1的性二态表达模式是男性与女性性腺发育的组成部分，是由SF-1启动子的性别特异性调节引起的。首先，我们将通过靶向雄性性腺外植体培养物中SF-1特异性siRNA来确定SF-1错误表达的后果（目的1）。其次，我们将评估雄性和雌性性腺外植体培养物中SF-1的5'调控区，以确定是否存在靶向基因性别特异性表达的特异性元件（目的2）。我们已经有效地消除了SF-1在siRNA处理的性腺中的存在，并且已经成功地将SF-1启动子构建体靶向到雄性和雌性中的正确细胞类型。这些研究是第一个已知的尝试，以调查SF-1的作用机制，在一个活的，完整的，功能正常的性腺，因为它是发展。这些研究结果将对我们目前对SF-1在性腺发育过程中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对已知和未知的基因进行新的研究，这将导致性腺发育领域的重大进展，并为治疗包括出生缺陷，不孕症和癌症在内的性腺异常提供希望。