Decoding GPCR signaling to understand chemotaxis

At every stage of our life, from embryonic development to ageing, the capability of cells to move is essential. During brain development, for instance, newly generated neurons need to correctly position within the brain to establish proper connections or, upon infection, motility of immune cells is indispensable to ensure host defense against intruding pathogens. To move within or across tissues and target their locations, cells typically use extracellular stimuli that provide important directions on the way to follow. This is known as directed migration - or chemotaxis - and is mediated by a defined class of proteins (so-called G-protein Coupled Receptors, GPCRs) located at the cell membrane. Such protein complexes translate extracellular guiding inputs into intracellular signals, making the cell move forward. Despite recent advancements in the field, little is known on the mechanisms that allow proper interpretation of chemotactic signals and that coordinate navigation through tissues. Here, we address these issues decoding the internal language of the cell (the GPCR signaling) and studying how multiple directives (signaling cascades) cooperate to ensure efficient directed migration. To this end, we will employ dendritic cells - motile cells of the immune system - and chemically/genetically interfere with their normal GPCR signaling functions while they are on the move. To examine their directional motility, we will combine several techniques in vivo and in vitro tailored to the analysis of different aspects of chemotaxis. In addition, biophysical manipulations will be useful to test how structural cell properties change upon alterations of GPCR signaling functions and how, in turn, this affects directed migration. Finally, we will apply state-of-the-art technologies to identify possible new players of the transducer machinery engaged in chemotaxis. Overall, our work will help us understand how different intracellular modules coordinate in space and time to guarantee coherence in cell movement. Also, it will broaden our current knowledge on how complex extracellular information is filtered and integrated to extract accurate directional information. Importantly, given the broad biological implications of both cell migration and GPCR signaling, our research will also be relevant for other scientific areas, like pharmacology, and provide insights on migration and spreading of cancer cells during metastasis.