La capacité remarquable des neurones et des cellules gliales à migrer collectivement sur de longues distances assure l’architecture finale du cerveau. Ce processus est extrêmement dynamique et dépend non seulement de l’interaction entre les cellules mais aussi de la présence de facteurs de transcriptions spécifiques au sein de la cellule migrante. Les protéines d’adhésion comme les cadhérines et les chimioattractants/chimiorépulsifs sont connus pour réguler et guider la migration. Si le mode d’action de ces molécules a été extensivement étudié, les cascades de signalisation qui déclenchent le chimiotropisme sont loin d’être élucidées. Au cours de mon doctorat, j’ai analysé la régulation et le rôle d’un récepteur des chimioattractant au cours de la migration de la glie. Pour ceci j’ai utilisé le modèle du développement de la chaine gliale dans l’aile de la drosophile qui représente un outil de choix pour étudier les mécanismes moléculaires régulant la migration collective. / The remarkable ability of neurons and glia to undergo long distance and collective migration ensures the final architecture and function of the brain. This is an extremely dynamic process that not only depends on cell interactions, but also on the presence of specific transcription factors in the migrating cells. Adhesion molecules such as classic cadherins and chemoattractants/repellants are known to regulate directional migration, however, how are these pathways regulated is largely unknown. While the role of these molecules controlling cell interactions has been extensively investigated, the signaling cascades that trigger chemotropism are not understood. During the course of my PhD I have analyzed the role of an adhesion molecule and the impact of a chemoattractant receptor regulated by an early transcription factor in the process. The glial chain in a developing Drosophila wing provides an excellent tool to study the molecular pathway underlying collective migration.

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Collective cell migration is a defining feature of many morphogenetic processes. Diseases such as congenital heart diseases and cancer arise due to mis-regulation of collective migratory behaviour and animal models have played a pivotal role in dissecting the molecular mechanisms which underlie this process. During embryonic heart development, cardiac precursors undergo a stage of collective migration in both vertebrates and invertebrates. We developed a paradigm to quantitatively assess collective cell migration of cardiac precursors in live embryos of Drosophila, which is the simplest genetic model organism with a heart. Therefore, we studied processes which are commonly observed in most collective cell migration models such as guidance signalling and extracellular matrix remodelling. Our results demonstrate that leading edge of migrating cardioblasts is highly active and that this behaviour is regulated by guidance cues, Slit and Netrin and their respective receptors Robo/Robo2 and Frazzled/Uncoordinated5. These molecules cooperatively promote leading edge motility and epithelial characteristics of the cardioblasts. Next, we determined that matrix restructuring around the cardioblasts requires proteases Mmp1 and Mmp2, which are members of the highly conserved Matrix Metalloproteinase family. We demonstrate that Mmp1 and Mmp2 have distinct roles during lumen formation, however, both Mmp1 and Mmp2 are required for collective motility of the cardioblast leading edge. Hence, we propose that embryonic heart development in Drosophila is an effective and amenable model of collective cell migration which can be applied to discover unique mechanisms which coordinate cell movement in groups. / Thesis / Doctor of Philosophy (PhD)

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