Transcriptional Determinants of Cell Differentiation

细胞分化的转录决定因素

• 批准号: 7236222
• 负责人: DANIEL L KILPATRICK
• 金额: $ 27.04万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236222
• 关键词: Adult; Alleles; Biochemical; Cell Differentiation process; Cells; Cholesterol; DNA Binding; Development; Energy Metabolism; Epitopes; Exhibits; Future; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Germ Cells; Goals; Haploidy; Individual; Localized; Male Contraceptive Agents; Male Infertility; Meiosis; Mus; Partner in relationship; Process; Property; Protein Isoforms; Response Elements; Role; Series; Somatic Cell; Spermatids; Spermatocytes; Spermatogenesis; Spermatogenic Cell; Staging; Sterols; Transfection; Transgenic Mice; Transgenic Organisms; base; in vivo; male; novel; null mutation; proacrosin; programs; promoter; recombinase; sperm cell; sperm function; transcription factor

DESCRIPTION (provided by applicant): Sperm are highly specialized cells and express numerous cell-specific mRNAs required for their proper development and function. Many of these mRNAs are generated from germ cell-specific genes or promoters, and numerous transcription factors are uniquely enriched in spermatogenic cells. However, extremely little is currently known about the role of individual transcription factors in directing male germ cell differentiation, including the specific gene targets they regulate and their mutual transcriptional interactions. The long-term goal of this proposal is to elucidate the transcriptional network responsible for elaboration of the spermatogenic differentiation program. A particular emphasis is the identification of spermatogenic cell-specific transcription factors required for the differentiation of meiotic spermatocytes and haploid spermatids. We recently identified a unique, male germ cell-enriched form of the transcription factor, SREBP2, which is required for cholesterol and energy metabolism in somatic cells. This factor, SREBP2gc, possesses several cell-specific properties which suggest novel, stage-dependent functions during spermatogenesis. It is our hypothesis that spermatogenic cells have adapted the ubiquitously expressed SREBP2 transcription factor to regulate a totally distinct set of novel, cell-specific target genes that are important for germ cell differentiation. Recent findings now demonstrate that SREBP2gc regulates the germ cell-specific proacrosin gene promoter. The aims of this proposal are: 1) to determine the impact of perturbing SREBP2gc function on sperm formation and function as well as on germ cell-specific gene expression; 2) further characterize the transcriptional interactions between SREBP2gc and the mouse proacrosin promoter; and 3) generate transgenic mice expressing epitope-tagged SREBP2gc. These mice will be used to further examine direct target genes for SREBP2gc during spermatogenesis. These studies will greatly advance our understanding of the transcriptional program underlying the formation of sperm, and may reveal underlying mechanisms important in male infertility and for the development of male contraceptives.

描述（由申请人提供）：精子是高度特化的细胞，表达其正常发育和功能所需的大量细胞特异性 mRNA。许多这些 mRNA 是由生殖细胞特异性基因或启动子产生的，并且许多转录因子在生精细胞中独特富集。然而，目前人们对单个转录因子在指导雄性生殖细胞分化中的作用知之甚少，包括它们调节的特定基因靶标及其相互转录相互作用。该提案的长期目标是阐明负责制定生精分化程序的转录网络。特别强调的是减数分裂精母细胞和单倍体精子细胞分化所需的生精细胞特异性转录因子的鉴定。我们最近发现了一种独特的、富含雄性生殖细胞的转录因子 SREBP2，它是体细胞中胆固醇和能量代谢所必需的。该因子 SREBP2gc 具有多种细胞特异性特性，表明精子发生过程中具有新的阶段依赖性功能。我们假设生精细胞已经适应了普遍表达的 SREBP2 转录因子来调节一组完全不同的新型细胞特异性靶基因，这些基因对于生殖细胞分化很重要。最近的研究结果表明，SREBP2gc 调节生殖细胞特异性顶体蛋白原基因启动子。该提案的目的是：1) 确定扰乱 SREBP2gc 功能对精子形成和功能以及生殖细胞特异性基因表达的影响； 2) 进一步表征SREBP2gc与小鼠顶体蛋白原启动子之间的转录相互作用； 3)产生表达表位标记的SREBP2gc的转基因小鼠。这些小鼠将用于进一步检查精子发生过程中 SREBP2gc 的直接靶基因。这些研究将极大地增进我们对精子形成背后的转录程序的理解，并可能揭示男性不育症和男性避孕药开发中重要的潜在机制。