Regulation of germline proliferation and differentiation

生殖系增殖和分化的调节

• 批准号: 7650586
• 负责人: JUDITH KIMBLE
• 金额: $ 24.29万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650586
• 关键词: Address; Animals; Biological Process; Caenorhabditis elegans; Cancer Etiology; Cell Fate Control; Cells; Cues; Development; Differentiation and Growth; Distal; Dose; Event; Fogs; Foundations; Germ Cells; Health; Human; Individual; Infertility; Learning; Light; Link; Maintenance; Malignant Neoplasms; Meiosis; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Mitosis; Modeling; Molecular; Nematoda; Oocytes; Polynucleotide Adenylyltransferase; Proteins; RNA-Binding Proteins; Regenerative Medicine; Regulation; Reproductive Biology; Research; Role; Signal Transduction; Source; Stem cells; Tissues; Work; base; combinatorial; fly; injured; notch protein; public health relevance; research study; response; sperm cell; stem cell niche

DESCRIPTION (provided by applicant): The long-term objective of the proposed research is to elucidate cellular and molecular controls of growth and differentiation in the animal germline. The proposed experiments address three fundamental problems of reproductive biology. First, how are germ cells controlled to continue mitosis or enter meiosis? Second, how are germ cells controlled to differentiate as sperm or oocyte in response to somatic cues? Third, how are the transitions from germline stem cell to transit-amplifying cell and then to meiotic entry controlled by the stem cell niche? Our proposed experiments focus on the C. elegans nematode germline, which is superbly poised to address these fundamental problems with molecular clarity. The power of this model derives from its experimental tractability and the rich foundation already laid. A single cell, the distal tip cell (DTC), creates the stem cell niche and germ cell fates are controlled by an emerging network of conserved molecular regulators, including GLP-1/Notch signaling, FBF/PUF and FOG-1/CPEB RNA-binding proteins, the GLD-2 cytoplasmic poly(A) polymerase and MPK- 1/MAP kinase, among others. Indeed, where known, the conserved regulators retain conserved regulatory relationships and biological functions. For example, PUF proteins control germline stem cells in nematodes, flies and probably humans, and PUF proteins control MAP kinase expression in both nematodes and humans. Our specific aims will identify FBF target mRNAs and investigate conserved PUF controls of proliferation and differentiation; analyze the molecular mechanism by which FOG-1/CPEB controls both proliferation and differentiation in a dose-dependent manner; elucidate fog-3 regulation and investigate how FOG-3/Tob controls both proliferation and the sperm fate; investigate GLD-2 and its combinatorial control of germline fates; and investigate the Niche Region, the Transit Amplifying Compartment and their molecular regulation. The unifying theme is that the aims together will delineate how these conserved proteins work within a regulatory network to orchestrate germline growth and differentiation. Moreover, our studies promise to reveal general mechanisms that operate broadly in animal development, because of our focus on conserved regulators and their control of fundamental fate decisions. The elucidation of cellular and molecular controls of germline fate decisions will likely shed light on the mechanistic basis of germline cancers and infertility, two major health problems. Our studies may also impact use of germ cells as a potential source of stem cells for regenerative medicine. PUBLIC HEALTH RELEVANCE: This proposal investigates the molecular regulation of germline stem cells, germline transit-amplifying cells and the sperm/oocyte decision. Regulators of these germline fates, when defective, cause cancer or infertility, two major health problems. Moreover, germ cells may well be the ultimate source of stem cells for regenerative medicine to replace tissues in diseased or injured individuals.

描述（由申请人提供）：拟议研究的长期目标是阐明动物种系生长和分化的细胞和分子控制。提出的实验解决了生殖生物学的三个基本问题。首先，如何控制生殖细胞继续有丝分裂或进入减数分裂？第二，如何控制生殖细胞分化为精子或卵母细胞以响应体细胞信号？第三，从生殖系干细胞到转运扩增细胞再到减数分裂进入是如何由干细胞生态位控制的？我们提出的实验集中在秀丽隐杆线虫的生殖系，这是极好的准备解决这些基本问题与分子清晰度。这个模型的强大之处在于它在实验上的可操作性和已经奠定的丰富基础。单个细胞，远端尖端细胞（DTC），创造干细胞生态位，生殖细胞命运由一个新兴的保守分子调控网络控制，包括GLP-1/Notch信号，FBF/PUF和fog1 /CPEB rna结合蛋白，GLD-2细胞质多聚(A)聚合酶和MPK- 1/MAP激酶等。事实上，在已知的情况下，保守调节因子保留了保守的调节关系和生物学功能。例如，PUF蛋白控制线虫、苍蝇和可能的人类的种系干细胞，PUF蛋白控制线虫和人类的MAP激酶表达。我们的具体目标是鉴定FBF靶mrna，并研究保守的PUF对增殖和分化的控制；分析fog1 /CPEB以剂量依赖性方式控制增殖和分化的分子机制；阐明fog-3的调控机制，探讨fog-3 /Tob如何同时控制细胞增殖和精子命运；研究GLD-2及其对种系命运的组合控制；研究其生态位区、转运扩增区及其分子调控。统一的主题是，这些目标将共同描述这些保守蛋白质如何在调节网络中协调生殖细胞的生长和分化。此外，我们的研究有望揭示在动物发育中广泛运作的一般机制，因为我们关注保守的调节因子及其对基本命运决定的控制。阐明生殖系命运决定的细胞和分子控制可能会揭示生殖系癌症和不育这两个主要健康问题的机制基础。我们的研究也可能影响生殖细胞作为再生医学干细胞的潜在来源的使用。公共卫生相关性：本提案研究生殖系干细胞、生殖系转运扩增细胞和精子/卵母细胞决定的分子调控。这些生殖细胞命运的调节因子一旦出现缺陷，就会导致癌症或不孕，这是两大健康问题。此外，生殖细胞很可能是再生医学干细胞的最终来源，以取代患病或受伤个体的组织。