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Identification and role of lysophospholipids in germ cell and heart biology

Final Report Summary - LYSOPHOSPHOLIPIDS (Identification and role of lysophospholipids in germ cell and heart biology)

Project objectives

Signalling between cells regulates many aspects of their behaviour including differentiation, migration and survival. Although much work to date has focused on secreted protein factors, bioactive lipids also have potent effects on cells. One class of signalling lipids are the lysophospholipids, which include sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA). Both are secreted by, for example, stimulated platelet cells leading to migratory and proliferative effects on smooth muscle cells, endothelial cells and white blood cells.

The broad scope of this research was to identify new lipid mediators or new roles for lysophospholipid mediators that govern developmental processes and to understand how these lipids cause changes in cellular behaviour.

In Drosophila, lipid signalling is implicated in guiding the migration and survival of germ cells. Germ cells are the cells that will later differentiate into sperm and eggs and undergo a stereotyped migration during embryogenesis to associate with somatic cells of the gonad. Screens for genes that affect this migration have uncovered a role for lipid phosphate phosphatases (LPPs). These enzymes can dephosphorylate lysophospholipids such as sphingosine 1-phosphate and lysophosphatidic acid in vitro but no in vivo targets have been identified.

Previous work using insect and mammalian cells culture has shown that LPP action, as well as causing dephosphorylation, also leads to uptake of the lipid moiety. In this research, we have taken Drosophila germ cells from embryos and shown that they also take up exogenously applied lipids and that this is dependent on LPPs. We propose that this could provide a mechanism through which exogenous lipids can affect these cells and this may provide a general mechanism that is conserved in animals.

We have also examined the role of LPPs in other Drosophila tissues, namely the Drosophila tracheal system. The latest is the gaseous exchange system of the fly. We have shown a requirement of LPPs for the formation and/or maintenance of cell-cell junctions (the so called 'septate junctions') in the tracheal system. Without such junctions, components that should normally localise to the lumen of the tracheal system leak out into the rest of the embryo. This results in a defective tracheal system that is unable to fill with gas and fulfil its function.

Our research has generated a molecular target for the action of LPPs, namely the septate junctions. Recently published work on a mouse LPP has indicated that it is required in vascular endothelial cells and knockdown of LPPs in these cells causes haemorrhaging (reviewed in Ren et al. 2012 Biochimica et Biophysica Acta). Whilst the molecular targets causing this phenotype are not known, our work points to likely effects on tight junctions, the mammalian equivalent of the septate junctions. Taken together, we hope that LPPs and the lipid signals they regulate could provide therapeutic targets for bleeding disorders such as transfusion-related lung injury.

This work has directly led to three publications, one in the international peer-reviewed journal 'Development' (Company of Biologists). The second is a comment article in the journal 'Fly' (Landes Bioscience) and a book chapter in 'Lysophospholipid Receptors: Signaling and Biochemistry' to be published by John Wiley & Sons later this year.

The web address of our group is http://www.eb.tuebingen.mpg.de/research/research-groups/andrew-renault.html.