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 i s 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.
Germinomas, tumors of the germ line that develop outside of the testis and ovaries are thought to arise from defective embryonic germ cell migration. Here we use Drosophila germ cell migration to determine some of the fundamental mechanisms of cell migration in the context of a developing organism. We use genetic and biochemical approaches, live imaging and in vitro germ cell cultures to address how lipids and lipid modification provide migratory cues and how these signals are interpretated by the migrating germ cells.
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|Sanchez, Carlos G; Teixeira, Felipe Karam; Czech, Benjamin et al. (2016) Regulation of Ribosome Biogenesis and Protein Synthesis Controls Germline Stem Cell Differentiation. Cell Stem Cell 18:276-90|
|Lehmann, Ruth (2016) Germ Plasm Biogenesis--An Oskar-Centric Perspective. Curr Top Dev Biol 116:679-707|
|Teixeira, Felipe K; Sanchez, Carlos G; Hurd, Thomas R et al. (2015) ATP synthase promotes germ cell differentiation independent of oxidative phosphorylation. Nat Cell Biol 17:689-96|
|Malone, Colin D; Lehmann, Ruth; Teixeira, Felipe Karam (2015) The cellular basis of hybrid dysgenesis and Stellate regulation in Drosophila. Curr Opin Genet Dev 34:88-94|
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|Slaidina, Maija; Lehmann, Ruth (2014) Translational control in germline stem cell development. J Cell Biol 207:13-21|
|Hurd, Thomas Ryan; Leblanc, Michelle Gail; Jones, Leonard Nathaniel et al. (2013) Genetic modifier screens to identify components of a redox-regulated cell adhesion and migration pathway. Methods Enzymol 528:197-215|
|Lehmann, Ruth (2012) Germline stem cells: origin and destiny. Cell Stem Cell 10:729-39|
|Sano, Hiroko; Kunwar, Prabhat S; Renault, Andrew D et al. (2012) The Drosophila actin regulator ENABLED regulates cell shape and orientation during gonad morphogenesis. PLoS One 7:e52649|
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