Germ Cell Migration in Drosophila

果蝇生殖细胞迁移

• 批准号: 10286579
• 负责人: RUTH LEHMANN
• 金额: $ 26.9万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-02 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286579
• 关键词: Germ; Cell; Migration; Drosophila

DESCRIPTION (provided by applicant): Many aspects of development require the migration of individual cells through diverse and complex environments. In vertebrate embryos, for example, neural crest cells leave the developing central nervous system and migrate over long distances to give rise to such cell types as sensory neurons, facial cartilage and pigment cells of the skin. In adults, migratory cell types include the cells of the immune system, fibroblasts during wound healing, and cancer cells during metastasis. During directed cell migration, motile cells are guided along a particular path, they recognize guidance cues and translate them into directed movement. Finally, cells must be able to recognize their target tissue and stop migrating and cells that fail to reach their target have to be eliminated. Primordial germ cells provide an excellent model system for the analysis of directed cell migration. Many aspects of germ cell biology, such as their overall morphology and their curious migratory path toward the somatic components of the gonad are conserved throughout the animal kingdom. We have used Drosophila to identify signals produced by the soma that guide migrating germ cells. We find that lipid signaling plays a critical role for migrating primordial germ cells. This proposal aims to understand how lipid signaling and membrane composition affect germ cell migration and survival. The aim is to characterize the signaling processes within the germ cells and to determine the nature and distribution of the extracellular signals that guide germ cells. In the first aim we will use a genetic approach targeted at germline expressed genes to identify new and additional components of the migratory machinery in germ cells. In the second aim, we will characterize the lipid targets of the Drosophila lipidphosphate phosphatases, Wunen and Wunen2 that guide germ cells and analyze the nature of the migratory response in germ cells and its role in germ cell survival. In the third aim, we propose to isolate a germ cell attractant produced by the somatic gonad, which we have shown is lipid modified and exported by the somatic gonad cells by an conserved, unconventional ABC transporter. Mis-migration of germ cells in humans is thought to be the cause of germinomas, tumors of the germ line that develop outside of the testis and ovaries. It remains unclear what causes germ cell mis-migration and why these apparently 'lost' germ cells survive outside of the gonad environment. The mechanisms underlying germ cell migration and survival have been studied in genetically tractable organisms such as Drosophila, mouse and zebrafish. These studies have revealed striking parallels in the behavior of germ cells and in the genes that control this behavior. Findings resulting from this application are likely to contribute to a better understanding of the cues and cellular processes that guide germ cell migration and that physically distinguish germ cells from other cells in the body.

描述（由申请人提供）：发育的许多方面都需要单个细胞在多样化和复杂的环境中迁移。例如，在脊椎动物胚胎中，神经嵴细胞离开正在发育的中枢神经系统，并长距离迁移，产生感觉神经元、面部软骨和色素细胞等细胞类型。 皮肤。在成人中，迁移细胞类型包括免疫系统细胞、伤口愈合期间的成纤维细胞和转移期间的癌细胞。在定向细胞迁移过程中，运动细胞沿着特定路径被引导，它们识别引导信号并将其转化为定向运动。最后，细胞必须能够识别其目标组织并停止迁移，并且必须消除未能到达目标的细胞。 原始生殖细胞为定向细胞迁移的分析提供了一个优秀的模型系统。生殖细胞生物学的许多方面，例如它们的整体形态和它们向性腺体细胞成分的好奇迁移路径，在整个动物界中都是保守的。我们使用果蝇来识别体细胞产生的引导生殖细胞迁移的信号。我们发现脂质信号传导对于原始生殖细胞的迁移起着关键作用。 这个提议 旨在了解脂质信号传导和膜组成如何影响生殖细胞迁移和存活。目的是表征生殖细胞内的信号传导过程，并确定引导生殖细胞的细胞外信号的性质和分布。在第一个目标中，我们将使用针对生殖系表达基因的遗传方法来识别生殖细胞中迁移机制的新的和额外的成分。在第二个目标中，我们将表征果蝇磷酸脂磷酸酶 Wunen 和 Wunen2 的脂质靶标，它们引导生殖细胞，并分析生殖细胞迁移反应的性质及其在生殖细胞存活中的作用。在第三个目标中，我们建议分离由体细胞性腺产生的生殖细胞引诱剂，我们已经证明它是由体细胞性腺细胞通过保守的、非常规的 ABC 转运蛋白进行脂质修饰和输出的。 人类生殖细胞的错误迁移被认为是生殖细胞瘤的原因，生殖细胞瘤是在睾丸和卵巢外发育的生殖系肿瘤。目前尚不清楚是什么原因导致生殖细胞错误迁移，以及为什么这些明显“丢失”的生殖细胞能够在性腺环境之外生存。生殖细胞迁移和存活的机制已经在果蝇、小鼠和斑马鱼等遗传易驯化的生物体中进行了研究。这些研究揭示了生殖细胞的行为和控制这种行为的基因之间惊人的相似之处。这项应用的发现可能有助于更好地理解指导生殖细胞迁移以及在物理上区分生殖细胞与体内其他细胞的线索和细胞过程。