Germ Cell Migration in Drosophila

描述（由申请人提供）：生殖细胞是维持所有有性生殖物种所必需的。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）的早期发育和它们分化成精子和卵子，在整个动物王国中是保守的。本提案侧重于分析PGC迁移。在大多数生物中，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性腺外生殖细胞肿瘤的起源。该提案结合了生物化学和遗传学方法与体内成像分析，以了解如何迁移线索整合超时和空间使用果蝇作为模型。将使用体内成像来跟踪生殖细胞在其通过后中肠的经上皮迁移期间的迁移路径以及其随后在野生型和突变体中朝向体细胞性腺的归巢。将分析G蛋白偶联受体（GPCR）Tre-1在启动迁移程序和跨上皮迁移中的作用。引诱剂和排斥体细胞的指导线索的分子性质将其特征在于通过研究先前确定的脂质磷酸酶途径的功能，由Wunen和Wunen 2，哺乳动物lipidphosphate phosphatase 3的两个同系物控制，并通过分析类异戊二烯途径，这是由HMGCoA还原酶控制。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Wunen和HMGCoA还原酶途径在索马体细胞中的体细胞信号传导的整合将得到解决。该提案的总体目标是将生殖细胞迁移的分子网络与发育胚胎的细胞参数联系起来。生殖细胞迁移行为的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共享。因此，对遗传上容易接受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普遍的原则。

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.