Germ Cell Migration in Drosophila

描述（由申请人提供）：生殖细胞是维持所有有性繁殖物种的必要条件。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。本文主要对PGC迁移进行分析。在大多数生物体中，PGCs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。这一过程受到复杂的调控，胚胎生殖细胞迁移的失败被归因于人类生殖道外生殖细胞肿瘤的起源。本研究将生物化学和遗传方法与体内成像分析相结合，以果蝇为模型，了解迁移线索是如何在时间和空间上整合的。在野生型和突变型中，体内成像将用于跟踪生殖细胞通过后中肠经上皮迁移和随后归巢到体细胞性腺的迁移路径。G蛋白偶联受体（GPCR） tre1将分析其在启动迁移程序和跨上皮迁移中的作用。通过研究先前发现的由哺乳动物脂质磷酸酶3的两个同源物Wunen和Wunen2控制的脂质磷酸酶途径的功能，以及通过分析由HMGCoA还原酶控制的类异戊二烯途径，来表征引诱剂和驱避剂体细胞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与生殖细胞中Wunen功能之间的相互作用，以及体细胞中Wunen和HMGCoA还原酶途径的体细胞信号传导整合将得到解决。本建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（如免疫系统细胞和转移性癌细胞）是相同的。因此，对果蝇生殖细胞系统的分析很可能揭示出控制细胞迁移的更普遍的原理。

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.