Germ Cell Migration in Drosophila

描述(申请人提供)：生殖细胞对维持所有有性繁殖物种是必不可少的。生殖细胞行为的许多细胞和分子方面，包括它们作为原始生殖细胞(PGCs)的早期发育以及它们向精子和卵子的分化，在整个动物界都是保守的。本提案重点分析了PGC的迁移问题。在大多数生物中，原生殖细胞起源于早期胚胎的一个地方，并通过胚胎迁移到性腺的体细胞部分，在那里它们分化。这一过程受到错综复杂的调控，胚胎生殖细胞迁移失败被归因于人类性腺外生殖细胞肿瘤的起源。这项建议将生化和遗传学方法与体内成像分析相结合，以果蝇为模型，了解迁徙线索是如何在时间和空间上整合的。活体成像将被用来跟踪生殖细胞在穿过中肠后上皮迁移过程中的迁移路径，以及随后在野生型和突变型生殖细胞中向体细胞性腺的归巢。G蛋白偶联受体(GPCR)，tre-1，将分析其在启动迁移程序和跨皮细胞迁移中的作用。通过研究以前发现的由哺乳动物磷脂磷酸酶3的两个同源物Wunen和Wunen2控制的脂磷酸酶途径的功能，以及通过分析由HMGCoA还原酶控制的异戊二烯途径，来表征引诱剂和排斥剂躯体引导线索的分子性质。随着对所涉及的途径的更详细的了解，GPCR和Wunen在生殖细胞中的功能之间的相互作用，以及通过Wunen和HMGCoA还原酶途径在胞体中整合体细胞信号将被解决。这项提议的总体目标是将生殖细胞迁移的分子网络与发育中的胚胎的细胞参数联系起来。生殖细胞迁移行为的某些方面与其他孤立的迁移细胞相同，例如免疫系统的细胞和转移的癌细胞。因此，对遗传上容易服从的果蝇生殖细胞系统的分析可能会揭示控制细胞迁移的更一般原理。

DESCRIPTION (provided by applicant): Germ cells are essential for the maintenance of all sexually reproducing species. Many cellular and molecular aspects of germ cell behavior including their early development as primordial germ cells (PGCs) and their differentiation into sperm and egg are conserved throughout the animal kingdom. This proposal focuses on the analysis of PGC migration. In most organisms PGCs originate at one place of the early embryo and migrate through the embryos to reach the somatic part of the gonad, where they differentiate. This process is intricately regulated and failures in embryonic germ cell migration have been attributed to the origin of extragonadal germ cell tumors in humans. This proposal combines biochemical and genetic approaches with in vivo imaging analysis to understand how migratory cues are integrated overtime and space using Drosophila as a model. In vivo imaging will be used to follow the germ cell migratory path during their transepithelial migration through the posterior midgut and their subsequent homing towards the somatic gonad in wild type and mutants. The G protein coupled receptor (GPCR), Tre-1, will be analyzed with regard to its role in initiating the migratory program and in transepithelial migration. The molecular nature of attractant and repellant somatic guidance cues will be characterized by studying the function of the previously identified lipid phosphatase pathway that is controlled, by Wunen and Wunen2, two homologs of mammalian lipidphosphate phosphatase 3, and by analyzing the isoprenoid pathway, that is controlled by HMGCoA reductase. With a more detailed knowledge of the pathways involved, the interplay between GPCR and Wunen function in germ cells, and the integration of somatic signaling by the Wunen and HMGCoA reductase pathways in the soma will be addressed. The overall goals of this proposal are to connect the molecular network of germ cell migration with the cellular parameters of the developing embryo. Aspects of germ cell migratory behavior are shared with other solitary migrating cells, such as cell of the immune system and metastasizing cancer cells. Thus, the analysis of the genetically easily amenable fruit fly germ cell system is likely to reveal more general principles controlling cell migration.