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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD041900-13
Application #
8727086
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2001-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
13
Fiscal Year
2014
Total Cost
$269,399
Indirect Cost
$109,991
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Slaidina, Maija; Lehmann, Ruth (2014) Translational control in germline stem cell development. J Cell Biol 207:13-21