Determining how membrane fluidity regulates embryonic cell migration

PROJECT SUMMARY/ABSTRACT Cells first interact with their environment through the plasma membrane where diverse interactions between lipids and proteins organize membrane complexes in response to external stimuli. One cellular behavior in which membrane organization plays a critical role is cell migration, wherein cells traverse complex three-dimensional landscapes to hone to new destinations. Cell migration events are at the root of many processes including embryonic tissue morphogenesis, immune cell surveillance, and cancer cell metastasis. Thus, a mechanistic understanding of how the plasma membrane is organized to orient cell migration is necessary for our appreciation of the basic principles of cell migration and for the identification and treatment of aberrant cell migration during human development and disease. While significant work has deciphered the adhesion, signaling, and mechanical proteins underlying migratory behaviors, we know far less about how individual lipids, and the biophysical properties they contribute to the membrane, regulate migratory behaviors. Research in our laboratory interrogates the role of lipid metabolism in regulating cell signaling, in vivo migration, and membrane fluidity with the ultimate goal of identifying new strategies to modulate aberrant cell migration during development and disease. We use the avian neural crest cell population as an ideal in vivo model to address these previously inaccessible questions due to their robust and synchronous migratory behavior, the ease by which they can be manipulated and visualized in vivo and measured for biophysical properties. Under this award we will answer the questions 1) how does membrane fluidity orient in vivo cell migration, and 2) how do cells regulate local membrane fluidity? We hypothesize that migrating cells undergo active lipid metabolism at the plasma membrane to tune local membrane fluidity, and that the organization of relative fluidity orients cell migration by positioning receptor proteins necessary for chemotaxis. We will test these hypotheses using in vivo and ex vivo live cell imaging, optogenetic approaches to locally alter membrane fluidity and protein localization, measuring transmembrane receptor protein diffusion rates, and performing targeted gene knockdown and mis-localization experiments. These projects will yield high-impact discoveries that shed new light on how to prevent cancer metastasis, improve wound healing and inflammation responses, and correct for atypical tissue morphogenesis. In addition, these experiments will reveal new directions for our lab as we continue to decipher how plasma membrane organization regulates cell signaling and migration.