Regulation of germline proliferation and differentiation

生殖系增殖和分化的调节

• 批准号: 7171503
• 负责人: JUDITH KIMBLE
• 金额: $ 20.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7171503
• 关键词: Address; Animals; Automobile Driving; Behavior; Bioinformatics; Biological Models; Caenorhabditis elegans; Cell Cycle; Cell Cycle Progression; Cells; Class; Development; Differentiation and Growth; Fertility; Gene Targeting; Genes; Genetic; Germ Lines; Growth; Human; Individual; Learning; Link; Meiosis; Mitosis; Mitotic; Molecular; Molecular Genetics; Nature; Nematoda; Notch Signaling Pathway; Oocytes; Organism; Pattern; Polynucleotide Adenylyltransferase; Proteins; RNA; RNA Interference; RNA-Binding Proteins; Regulation; Research; Role; Shapes; Signal Transduction; Site; Source; Stem cells; Tissues; Vertebral column; Work; base; genetic analysis; genome sequencing; glucagon-like peptide 1; injured; intercellular communication; research study; size; sperm cell

DESCRIPTION (provided by applicant): A central problem in metazoan development is how cells are governed to grow or differentiate in a tissue-specific pattern. We propose to analyze the genetic and molecular basis of this fundamental problem in the germ line of the nematode Caenorhabditis elegans. The C. elegans germ line is particularly suitable for these studies because of its powerful genetics, completed genome sequence, and cellular simplicity. A single somatic regulatory cell serves as a "niche" for germline stem cells, and this cell promotes germline proliferation by the conserved GLP-1/Notch signaling pathway. Moreover, the mitosis/meiosis decision is controlled, at least in part, by RNA-binding proteins of four conserved classes (Puf, Nanos, STAR/quaking, Bic-C) plus a newly discovered cytoplasmic poly(A) polymerase. In the next five years, we propose to analyze mechanisms by which central players of germline control (GLP-1 signaling/RNA regulators) are able to orchestrate growth of the germ line and specification of the mitosis/meiosis decision. First, we will identify genes directly controlled by GLP-1 signaling to promote germline mitoses. This work is predicted to link GLP-1 signaling with the RNA regulatory network and perhaps with the cell cycle machinery driving mitosis. Second, RNA regulators will be analyzed with respect to their relationship to GLP-1 signaling, their relationships among each other and their target mRNAs. This work is predicted to delineate the backbone of the genetic circuit controlling germline growth and the switch into the meiotic cell cycle. Third, additional regulators will be identified and investigated to learn their genetic and molecular relationships with the known central players. To this end, we propose to combine bioinformatics, RNAi and traditional genetics. Fourth, the nature of germline stem cells within the germline mitotic region will be investigated. Finally, the molecular circuit controlling germline growth and differentiation will be linked to cellular behaviors in the mitotic germ line, including cell cycle progression and tissue shape. The proposed studies will serve as a paradigm for developmental controls in higher organisms, including humans. The health-relatedness of this work is two-fold. First, the germ line holds the key to fertility. Second, germline stem cells may be the ultimate source of stem cells for tissue replacement in diseased or injured individuals.

描述（由申请人提供）：后生动物发育的一个中心问题是如何控制细胞以组织特异性模式生长或分化。我们建议分析秀丽隐杆线虫种系中这一基本问题的遗传和分子基础。线虫种系因其强大的遗传学、完整的基因组序列和细胞简单性而特别适合这些研究。单个体细胞调节细胞充当生殖系干细胞的“生态位”，该细胞通过保守的 GLP-1/Notch 信号通路促进生殖系增殖。此外，有丝分裂/减数分裂的决定至少部分地由四个保守类别（Puf、Nanos、STAR/quaking、Bic-C）的RNA结合蛋白以及新发现的细胞质poly(A)聚合酶控制。 在接下来的五年中，我们建议分析种系控制的核心参与者（GLP-1信号/RNA调节剂）能够协调种系生长和有丝分裂/减数分裂决定的规范的机制。首先，我们将鉴定直接受 GLP-1 信号控制以促进种系有丝分裂的基因。这项工作预计将 GLP-1 信号传导与 RNA 调节网络以及驱动有丝分裂的细胞周期机制联系起来。其次，将分析 RNA 调节因子与 GLP-1 信号传导的关系、它们之间的关系以及它们的目标 mRNA。这项工作预计将描绘出控制种系生长和进入减数分裂细胞周期的遗传回路的主干。第三，将确定和研究其他监管机构，以了解它们与已知核心参与者的遗传和分子关系。为此，我们建议将生物信息学、RNAi 和传统遗传学结合起来。第四，将研究生殖系有丝分裂区域内生殖系干细胞的性质。最后，控制种系生长和分化的分子回路将与有丝分裂种系中的细胞行为相关，包括细胞周期进程和组织形状。 拟议的研究将作为包括人类在内的高等生物发育控制的范例。这项工作与健康的相关性有两个方面。首先，种系是生育能力的关键。其次，生殖系干细胞可能是用于患病或受伤个体组织替代的干细胞的最终来源。