Environmental cues regulating primordial germ cell development

调节原始生殖细胞发育的环境因素

• 批准号: 7804609
• 负责人: RONALD A. CONLON
• 金额: $ 29.98万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804609
• 关键词: Ablation; Adhesives; Adult; Affect; Apoptosis; Behavior; Binding; Binding Sites; Biological Assay; Blood Cells; Brain; Cell Count; Cell Survival; Cell Transplantation; Cells; Characteristics; Cues; Data; Development; Disease; Disease Progression; Embryo; Embryonic Structures; Enhancers; Environment; Epithelium; Erythrocytes; Family; Female; Gene Targeting; Genes; Genital system; Germ Cells; Germ cell tumor; Goals; Gonadal structure; Human; Infertility; Injury; Intestines; Introns; KITLG gene; Life; Light; Longevity; MAPK14 gene; Malignant Neoplasms; Meiosis; Mesenchyme; Methods; Mitotic; Molecular and Cellular Biology; Mus; Nucleic Acid Regulatory Sequences; Organ Culture Techniques; Organism; Pathway interactions; Play; Pluripotent Stem Cells; Population; Population Control; Process; Proliferating; Regulatory Element; Reporter; Research Personnel; Role; Signal Transduction; Site; Skin; Somatic Cell; Speed; Stem Cell Development; Stem cells; Structure of primordial sex cell; System; Tamoxifen; Testing; Testis; Therapeutic; Tissue Transplantation; Tissues; Transplantation; Urogenital ridge structure; bone; cell behavior; cell motility; cell type; cytokine; falls; in vivo; insight; male; migration; neuronal cell body; novel; programs; promoter; research study; stem cell division; stem cell niche; stem cell population

DESCRIPTION (provided by applicant): Pluripotent stem cells can divide and differentiate to give rise to multiple cell types. These cells have enormous therapeutic potential for replacing tissue loss caused by disease or injury. To harness this potential, it is vital to understand the signaling interactions that control stem cell behavior in vivo. PGCs are the pluripotent cell population that will give rise to the gametes. Using a line of mice expressing the live cell marker GFP under control of a germ cell specific promoter, it is now possible to directly observe the behavior of living primordial germ cells as they migrate towards and colonize the embryonic gonads. This assay provides a novel opportunity to test how PGCs interact with their environment. Data from this assay has demonstrated that the bone morphogenetic family plays a pivotal role in PGC migration. Also, preliminary data indicates that BMPs regulate expression of a network of genes within the soma and within PGCs that control PGC numbers, motility, and ability to differentiate. This study will test the role of BMP signaling in PGC migration using temporal and tissue specific gene targeting in the mouse (Aim 1). BMP-responsive regulatory elements will be identified in the Kitl gene (Aim 2). Finally, cell transplantation assays and ablation experiments will be used to examine how different environments affect PGC behavior (Aims 3 and 4). Our ultimate goal is to understand the cellular and molecular interactions that control PGC migration and differentiation. This study will provide insight into how stem cell development is coordinated. Additionally, errors in PGC migration contribute to human infertility and germ cell tumors. Data from this study will shed light on these processes.

描述（由申请人提供）：多能干细胞可以分裂和分化以产生多种细胞类型。这些细胞具有巨大的治疗潜力，可以替代疾病或损伤引起的组织损失。为了利用这种潜力，了解控制体内干细胞行为的信号相互作用至关重要。 PGC 是产生配子的多能细胞群。使用在生殖细胞特异性启动子控制下表达活细胞标记 GFP 的小鼠系，现在可以直接观察活原始生殖细胞在向胚胎性腺迁移并定殖时的行为。该测定提供了测试 PGC 如何与其环境相互作用的新机会。该测定的数据表明，骨形态发生家族在 PGC 迁移中发挥着关键作用。此外，初步数据表明，BMP 调节体细胞内和 PGC 内基因网络的表达，控制 PGC 数量、运动性和分化能力。本研究将使用小鼠的时间和组织特异性基因靶向来测试 BMP 信号传导在 PGC 迁移中的作用（目标 1）。将在 Kit1 基因中鉴定 BMP 响应性调控元件（目标 2）。最后，细胞移植测定和消融实验将用于检查不同环境如何影响 PGC 行为（目标 3 和 4）。我们的最终目标是了解控制 PGC 迁移和分化的细胞和分子相互作用。这项研究将深入了解干细胞发育是如何协调的。此外，PGC 迁移错误会导致人类不育和生殖细胞肿瘤。这项研究的数据将揭示这些过程。