Environmental cues regulating primordial germ cell development

描述(申请人提供)：多能干细胞可以分裂和分化，形成多种细胞类型。这些细胞具有巨大的治疗潜力，可以取代因疾病或损伤而导致的组织丢失。为了利用这一潜力，了解控制体内干细胞行为的信号相互作用是至关重要的。原生殖细胞是产生配子的多能细胞群体。利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，现在可以直接观察活的原始生殖细胞向胚胎性腺迁移和定植时的行为。这项测试提供了一个新的机会来测试PGCs如何与环境相互作用。本实验数据表明，骨形态发生家族在PGC迁移过程中起着关键作用。此外，初步数据表明，BMP调节胞体内和PGC内控制PGC数量、运动性和分化能力的基因网络的表达。这项研究将利用小鼠的时间和组织特异性基因靶向来测试BMP信号在PGC迁移中的作用(目标1)。骨形态发生蛋白反应的调控元件将在Kitl基因中确定(AIM 2)。最后，将使用细胞移植试验和消融实验来检验不同环境如何影响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。这项研究将为干细胞发育如何协调提供洞察力。此外，PGC迁移错误会导致人类不孕不育和生殖细胞肿瘤。这项研究的数据将揭示这些过程。

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.