Directional cell migration is required in a vast array of biological mechanisms, including organogenesis, proper immune system function, and tumor metastasis. To accomplish migration, individual cells respond to highly regulated signaling cues which mediate downstream cytoskeletal remodeling events in order to form polarized protrusions and shape changes, all while establishing and maintaining interactions with the extracellular environment. However, the mechanisms that underlie collective cell migration are less well understood, and involve not only the morphogenetic changes involved in single cell migration, but also require the maintenance of cell-cell junctions during movement. Additionally, cell shape changes and establishment of polarity must be coordinated in a multicellular manner in order to preserve directional movement in the migrating cohort. In embryos of the fruit fly Drosophila melanogaster, the caudal visceral mesoderm (CVM) cells are muscle founders specified in the embryo at its posterior-most end. These cells undergo the longest migration of any cell type in Drosophila and undergo synchronous bilateral migration, thus serving as a simple model for collective cell migration. The Stathopoulos laboratory has previously reported a role for FGF signaling in ensuring proper bilateral movement of the two groups of CVM cells, and recent gene expression profiling and RNAi experiments have uncovered genes that exhibited CVM migration defects. Furthermore, we have evidence that primordial germ cell (PGC) and CVM cell migration may be interdependent, and preliminary analysis suggests that Wnt/Fz signaling plays a role in supporting this process. I hypothesize that spatiotemporal expression and localization of signaling factors by the CVM cells in conjunction with graded signaling cues from surrounding tissues (including the germ cells) mediate their migration - specifically, that a subset of cells within the migrating collective responds to cell autonomous and non-cell autonomous Wnt cues in order to mediate forward migration and repulsive exclusion from the midline. I will use a combination of genetic and immunohistochemistry approaches in conjunction with in vivo live imaging and a novel conditional knockout system to investigate the contribution of Wnt/Fz signaling to CVM cells, the interdependence of CVM and PGC migration, and leader and follower cell dynamics within a migrating collective. This study will address the gap in the literature regarding how distinct tissues can cooperatively influence migration, as well as contribute to a general understanding of how subsets of cells within a group respond to signaling cues. The insights gained from this study will also prove useful in understanding the mechanisms underlying tumor metastasis, with the ultimate goal of identifying potential therapeutic targets.
Collective migration of groups of cells is critical to the formation of various tissues and organs, and the means by which such cells integrate autonomous and non-autonomous cues from the environment is not well understood. I will use Drosophila caudal visceral mesoderm (CVM) cells as a simple model for collective migration, and I will test the contribution of Wnt/Fz signaling and neighboring cells in mediating their forward movement. This study will contribute to the general understanding of how subtypes of cells within a cohort can promote forward migration, as well as how interdependent migration between two distinct groups of cells is accomplished.
| Bae, Young-Kyung; Macabenta, Frank; Curtis, Heather Leigh et al. (2017) Comparative analysis of gene expression profiles for several migrating cell types identifies cell migration regulators. Mech Dev 148:40-55 |
