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Guidance Mechanisms of Cell Migration

Final Report Summary - GMCM (Guidance Mechanisms of Cell Migration)

Directed cell migration is a crucial process both in health and disease. The basic features of how a cell moves have been well characterized in tissue culture systems; however, how cells interact with the environment in vivo and how these complex interactions shape their behavior are less well understood. Cells migrating in vivo transiently adhere to several tissues of different chemical and mechanical properties and encounter other signals and barriers that are in place for other simultaneous processes. This complexity and inherent “noise” requires each cell to have mechanisms to incorporate and codify all parameters (molecular, cellular, physical) and translate them into cell shape changes and directed movement. Although the simplicity of in vitro systems has greatly advanced our understanding of migration, only advanced live imaging, coupled with genetic manipulation, will allow the full comprehension of how a cell acts in the body of an animal, be it Drosophila or the human body.
We use primordial germ cells (PGC) in the Drosophila embryo as a model system in which to explore these questions.
Moreover, PGC are fundamental cells in all animals as fertility and maintenance of the species depend on egg and sperm production, which, in turn, depend on the association of PGC and somatic cells of the gonad.
As such the study of PGC migration during development allows us to probe single cell migration as well as what regulates fertility.
I had previously shown that PGC guidance to the somatic gonad is dependent on the production of a lipid-modified (prenylated) chemoattractant, modified by the prenyl protease Dste24 and not Sras (Rce-1 like) and exported by an ABC transporter (Mdr49) expressed in the somatic gonad. This work has demonstrated a novel function in multicellular organisms of a highly conserved pathway that produces and exports prenylated signals.
The main goals of this project were 1. To understand single cell motility and guidance during the migratory cells interactions with the tissue microenvironment in vivo, using PGCs as a model system, 2. The novel role of the conserved class of ABC transporters, Multi Drug Resistance (Mdr), commonly recognized as toxin extruders, in cell migration. 3. To identify the ste24/mdr dependent prenylated substrates.
During the time of the Marie Curie Action we completed and published one project, are finishing a second one and aim to complete a third one in the next year.
We constructed a three dimensional map of PGC movement and show, by tracking a large number of PGCs by live imaging, that PGCs migrate as independent units but forming three subsets with distinct success in forming the gonad. This work is in its concluding phase.
In the first two years we had initiated the ambitious projected objective of identifying the PGC prenylated attractant. We have also initiated work aimed at identifying ste24/ hmgcr dependent prenylome, using two-step chemical labeling technology.
Additionally, we published work in which we show that FGF dependent E-cadherin targeting in the midgut is necessary to maintain its three-dimensional shape and efficient PGC movement.

Sara Ricardo (Ramon y Cajal Principal Investigator)
Tel: +34 93 403 4702
Fax: +34 93 403 4979

Instituto Biologia Molecular de Barcelona (IBMB) /CSIC
Parc Cientific de Barcelona
Carrer Baldiri Reixac, 10-12
Barcelona 08028