Androgen-Dependent Rhox Homeobox Genes

雄激素依赖性 Rhox 同源盒基因

• 批准号: 7805635
• 负责人: MILES Frome WILKINSON
• 金额: $ 31.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-07 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805635
• 关键词: Agreement; Androgen Receptor; Androgen Response Element; Androgens; Binding; Contraceptive methods; Development; Elements; Epididymis; Event; Family member; Figs - dietary; Future; Gene Cluster; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Germ Cells; Goals; Homeobox Genes; In Vitro; Lead; Male Contraceptive Agents; Male Infertility; Mediating; Meiosis; Molecular; Mus; Names; Nuclear Hormone Receptors; Ovary; Participant; Placenta; Published Comment; Reproduction; Research Personnel; Role; Sperm Maturation; Spermatids; Spermatogenesis; Testis; Time; Uncertainty; Work; X Chromosome; base; cell type; in vivo; interest; male; member; novel; postnatal; programs; receptor expression; reproductive; response; selective expression; sertoli cell; sperm cell; transcription factor

DESCRIPTION (provided by applicant): Spermatogenesis has been known for decades to depend on androgens, but the molecular mechanism behind this has remained largely elusive. Even the cell types in the testis that drive spermatogenesis in response to androgens had not been clearly defined until recent mouse genetic studies demonstrated that at least one participant is the Sertoli cell. It is logical that the Sertoli cell would promote spermatogenesis in response to androgens, as it is in intimate contact with developing germ cells and expresses high levels of androgen receptor (AR), a nuclear hormone-receptor family member and transcription factor that must usually be bound to androgen to activate its target genes. Most androgen-regulated genes in Sertoli cells may not be direct targets of AR but instead may be regulated by androgen-regulated transcription factors. These secondary androgen-response genes have cis elements that bind to androgen-regulated transcription factors. To date, no transcription factors regulating these secondary androgen-response genes in Sertoli cells have been definitively identified. A good candidate is the founding member of the Rhox homeobox gene cluster, Rhox5 (Pem), as it is androgen regulated, selectively expressed in Sertoli cells, and necessary for normal spermatogenesis. This proposal focuses on two other androgen-regulated genes in the Rhox homeobox gene cluster, Rhox10 and Rhox11. Each is expressed at peak levels in the testes at postnatal time points that correspond to two distinct AR-dependent events during spermatogenesis: the progression of male germ cells through meiosis I and the transition of late-round spermatids into elongating spermatids. Thus, we hypothesize that Rhox10 and Rhox11 encode transcription factors that participate in mediating these two AR-dependent events. The Specific Aims of this application are (i) to identify the functions of the androgen-regulated Rhox10 and Rhox11 genes in spermatogenesis and sperm maturation in vivo; (ii) to distinguish the independent and redundant roles of the androgen-regulated Rhox5, Rhox10, and Rhox11 genes in male reproduction; and (iii) to begin to elucidate the AR-dependent gene networks that drive spermatogenesis by identifying gene targets of the androgen-regulated Rhox genes. By providing a molecular basis for androgen-driven spermatogenesis, the proposed work could ultimately lead to cures for some cases of male infertility and the development of novel male contraceptive methods.

描述（由申请人提供）：几十年来，人们已经知道精子发生依赖于雄激素，但其背后的分子机制在很大程度上仍然难以捉摸。即使睾丸中响应雄激素而驱动精子发生的细胞类型也尚未明确定义，直到最近的小鼠遗传学研究证明至少一个参与者是支持细胞。顺理成章的是，支持细胞会响应雄激素而促进精子发生，因为它与发育中的生殖细胞密切接触，并表达高水平的雄激素受体（AR），雄激素受体是一种核激素受体家族成员和转录因子，通常必须与雄激素结合才能激活其靶基因。支持细胞中的大多数雄激素调节基因可能不是 AR 的直接靶标，而是可能受到雄激素调节转录因子的调节。这些次级雄激素反应基因具有与雄激素调节转录因子结合的顺式元件。迄今为止，尚未明确鉴定出调节支持细胞中这些次级雄激素反应基因的转录因子。一个很好的候选者是 Rhox 同源盒基因簇的创始成员 Rhox5 (Pem)，因为它受雄激素调节，在支持细胞中选择性表达，并且是正常精子发生所必需的。该提案重点关注 Rhox 同源盒基因簇中的另外两个雄激素调节基因，Rhox10 和 Rhox11。每一种在出生后时间点在睾丸中表达达到峰值水平，对应于精子发生过程中两个不同的 AR 依赖性事件：雄性生殖细胞通过减数分裂 I 的进展以及晚轮精子细胞向伸长精子细胞的转变。因此，我们假设 Rhox10 和 Rhox11 编码参与介导这两个 AR 依赖性事件的转录因子。本申请的具体目标是（i）确定雄激素调节的Rhox10和Rhox11基因在体内精子发生和成熟中的功能； (ii) 区分雄激素调节的 Rhox5、Rhox10 和 Rhox11 基因在雄性生殖中的独立和冗余作用； (iii) 通过识别雄激素调节的 Rhox 基因的靶标，开始阐明驱动精子发生的 AR 依赖性基因网络。通过为雄激素驱动的精子发生提供分子基础，拟议的工作最终可能会治愈某些男性不育症并开发新型男性避孕方法。