RING OR ZINC FINGER PROTEINS DURING GAMETOGENESIS AND EMBRYONIC DEVELOPMENT

配子发生和胚胎发育过程中的环或锌指蛋白

• 批准号: 7720694
• 负责人: ZI-JIAN LAN
• 金额: $ 10.73万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720694
• 关键词: Ablation; Address; Amino Acids; Apoptosis; Binding; C2H2 Zinc Finger; Cell Cycle Progression; Cell physiology; Cessation of life; Chromatin; Chromosomes; Class; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Contraceptive Agents; Cysteine; DNA Repair; Databases; Defect; Development; Development, Other; Diagnostic Reagent; Disease; Embryo; Embryonic Development; Event; Expressed Sequence Tags; Female; Fertility; Fingers; Funding; Gametogenesis; Gene Expression; Gene Expression Regulation; Generations; Genes; Genomics; Germ Cells; Grant; Histidine; Homologous Gene; Human; Infertility; Institution; Ions; Knowledge; Lead; Maintenance; Male Infertility; Malignant Neoplasms; Mammary gland; Medicine; Meiosis; Molecular Genetics; Mus; NEURL gene; Names; Numbers; Oocytes; Orthologous Gene; Pattern; Phenotype; Physiological; Play; Pregnancy; Process; Proteins; Research; Research Personnel; Resources; Ring Finger Domain; Role; Role playing therapy; Signal Transduction; Somatic Cell; Source; Spermiogenesis; Stem cells; Structure; Transcription Coactivator; Ubiquitination; United States National Institutes of Health; Variant; Zinc; Zinc Fingers; base; cDNA Library; cell growth; cofactor; genome database; interest; male; novel; novel therapeutics; protein degradation; reproductive; reproductive development; tumorigenesis; ubiquitin-protein ligase; zygote

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Reproductive development and function are complex processes involving both genetically determined and physiological events. Identification of the critical genes involved in regulating these processes is necessary to characterize how these processes are coordinated. In particular, the generation of mature gametes involves many steps of development and differentiation, as well as the distinctive cellular process meiosis, that are collectively termed gametogenesis. In general, differentiation and development, and other processes that lead to the acquisition and maintenance of a cellular phenotype are dependent on the differential and coordinate regulation of gene expression. However, the regulation of gene expressioin many aspects of gametogenesis such as proliferation of spermatogonial stem cells, signals for meiotic arrest and meiotic exit, and spermiogenesis, and cross-talk between germ cells and adjacent somatic cells, are not clearly understood. In addition, the roles of maternal and paternal genes in zygotic development are also not well defined. Identification and functional characterization of germ cell-specific molecules such as zinc finger proteins during gametogenesis and early embryonic development would advance our knowledge regarding gamete and zygotic development, and will provide new leads for development of diagnostic reagents for reproductive diseases, novel therapeutic medicines for the treatment of infertility, gonadal cancers, pre-natal death, and novel contraceptive agents. The RING (Really interesting novel genes) finger is a specialized type of zinc finger proteins. It contains an evolutionarily conserved structure found in more than 300 proteins from the human genome database, in which two loops of amino acids are pulled together at their base by eight cysteine or histidine residues that bind two zinc ions. There are two different variants, the C3HC4-type and the C3H2C3-type, which is clearly related despite the different cysteine/histidine patterns. These ring finger domains are found in two major classes of proteins: (1) transcriptional activators, repressors or cofactors and (2) subunits of complexes that modulate chromatin. These proteins likely interact with other proteins, participate in ubiquitination, and play roles in cell growth control such as apoptosis, tumorigenesis, DNA damage repair, and gene expression. In silico analyses have demonstrated that a large number of ring/zinc finger proteins with human homologs are expressed in the germ cells or early embryos, indicating that these proteins may play a role in germ cell and zygotic development. Recent studies have shown that ring finger proteins, zygote arrest 1 (Zar1) and NEURL are critical for zygotic development, and male fertility and mammary gland maturation during pregnancy, respectively. Ablation of another ring finger protein, Siah1a, also caused male infertility due to defects in meiosis. In addition, another oocyte specific ring finger protein, RFPL4, interacts with oocyte proteins and likely functions as an E3 ubiquitin protein ligase to regulate protein degradation and meiotic cell cycle progression. Therefore, we are just in the beginning to understand the functional roles of these ring/zinc finger proteins during gametogenesis and early embryonic development. Having searched mouse and human genomic databases, I found that seven uncharacterized genes likely play a role during gametogenesis and zygotic development, as the expressed sequence tags (ESTs) of these genes are present in the cDNA libraries of mouse, human germ cells or early embryos. I am particularly interested in five of these genes (named unknown 1-5), which are located in different mouse chromosomes and all have human orthologs. Unknown-1, -2 and -3 are C3HC4 ring finger proteins, while unknown?4 and ?5 are C2H2 zinc finger proteins, similar to zfp148, nanos2 and nanos3, which are required for male or female germ cell development. I will combine genetic, molecular, and cellular approaches to address whether these genes are involved in the gametogenesis and early embryonic development.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 生殖发育和功能是一个复杂的过程，涉及遗传决定和生理事件。鉴定参与调节这些过程的关键基因对于表征这些过程是如何协调的是必要的。特别是，成熟配子的产生涉及许多发育和分化步骤，以及独特的细胞过程减数分裂，统称为配子发生。一般而言，分化和发育以及导致细胞表型的获得和维持的其他过程依赖于基因表达的差异和协调调节。然而，在配子发生的许多方面，如精原干细胞的增殖，减数分裂阻滞和减数分裂退出的信号，精子发生，以及生殖细胞和相邻体细胞之间的串扰，基因表达的调控还不清楚。此外，母本和父本基因在合子发育中的作用也没有很好的定义。生殖细胞特异性分子如锌指蛋白的鉴定和功能表征 配子发生和早期胚胎发育将推进我们关于配子和合子发育的知识，并将为生殖疾病诊断试剂的开发提供新的线索，用于治疗不孕症，性腺癌，产前死亡和生殖系统疾病的新型治疗药物。 新型避孕药。 RING（Really Interesting Novel Genes）指是一种特殊类型的锌指蛋白。它包含一种在人类基因组数据库中的300多种蛋白质中发现的进化保守结构，其中两个氨基酸环在其碱基处被8个半胱氨酸或组氨酸残基拉在一起，这些残基结合两个锌离子。有两种不同的变体，C3HC4型和C3H2C3型， 尽管半胱氨酸/组氨酸模式不同，但这显然是相关的。这些环指结构域存在于两大类蛋白质中：（1）转录激活因子、阻遏物或辅因子和（2）调节染色质的复合物的亚基。这些蛋白质可能与其他蛋白质相互作用，参与遍在蛋白化，并在细胞生长控制（例如细胞凋亡、肿瘤发生、DNA损伤修复和基因表达）中发挥作用。计算机模拟分析表明，大量的环/锌指蛋白与人类同源物在生殖细胞或早期胚胎中表达，表明这些蛋白可能在生殖细胞和合子发育中发挥作用。最近的研究表明，环指蛋白，受精卵阻滞1（Zar 1）和NEURL是至关重要的合子发育，男性生育力和乳腺成熟在怀孕期间，分别。另一种无名指蛋白Siah1a的消融也会导致减数分裂缺陷导致男性不育。此外，另一种卵母细胞特异性环指蛋白RFPL 4与卵母细胞蛋白相互作用，并可能作为E3泛素蛋白连接酶来调节蛋白质降解和减数分裂细胞周期进程。因此，我们才刚刚开始了解这些环/锌指蛋白在配子发生和早期胚胎发育中的功能作用。 在搜索小鼠和人类基因组数据库后，我发现7个未表征的基因可能在配子发生和合子发育过程中发挥作用，因为这些基因的表达序列标签（EST）存在于小鼠，人类生殖细胞或早期胚胎的cDNA文库中。我对其中的五个基因（命名为未知1 - 5）特别感兴趣，它们位于不同的小鼠染色体上，并且都具有人类直系同源物。Unknown-1、-2和-3是C3HC4环指蛋白，而Unknown？4、？5是C2H2锌指蛋白，类似于zfp148，nanos2和nanos3，它们是男性或女性生殖细胞发育所必需的。我会将遗传分子和细胞的联合收割机 研究这些基因是否参与配子发生和早期胚胎发育的方法。