Investigating how sequentially acting cues guide long-distance cell migration in vivo within embryos

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SUMMARY Collective cell migration is essential to the progression of normal embryonic development and organogenesis, and is a tightly-regulated process that can involve the interplay between two or more signaling pathways to drive forward movement of cell cohorts. Additionally, patterning an organ often requires selective apoptosis and compensatory proliferation of cells. Errors in collective migration and cell death programs can have serious consequences, including complete developmental arrest, abnormal organ function, and tumorigenesis. In this proposed research plan, we will use the Drosophila embryonic caudal visceral mesoderm (CVM), a small population of muscle precursor cells that undergo highly stereotyped directional movement, as a model for collective cell migration and survival. As the longest migration of embryogenesis, CVM cells must receive input via signaling cues from other cells in order to navigate the changing environment of the developing embryo. We have previously determined an important role for FGF signaling as both chemotropic and survival cue, and that FGF receptor is specifically expressed in a subset of migratory cells. However, loss of FGF signaling does not completely ablate collective migration, suggesting the existence of additional, as-of-yet uncharacterized cues. The objective of this study is to gain a comprehensive understanding of the spatiotemporally-regulated cues that guide directional movement of the CVM, and subsequent survival or apoptosis of distinct subsets of cells. Our central hypothesis is that FGF signaling cooperates with additional signaling cues in order to drive forward movement and cell survival, and involves defining specialized subsets of cells within each CVM cohort to promote spatial organization driving forward movement. To test this hypothesis, we will pursue the following specific aims: (AIM 1) Investigate roles for spatially-localized genes within the migrating CVM collective in promoting cell migration; (AIM 2) Investigate mechanism of CVM attraction to PGCs; and (AIM 3) Investigate the relationship between BMP and FGF signaling in regulating CVM cell migration and survival. To accomplish these aims, we will employ an innovative combination of established genetics and immunostaining techniques with elegant optogenetics and in vivo live imaging approaches to manipulate and visualize migratory cells, as well as quantify spatiotemporal activation of the cell death program. We believe this study is significant because it would not only demonstrate a mechanism for signaling cross-talk in an emerging yet poorly-characterized cell migration system, but considering the large number of functions and diseases attributed to signaling pathways such as BMP and FGF, elucidating the interaction between multiple pathways in the context of the genetically-tractable and conserved Drosophila model system has the potential to identify more specific therapeutic targets. Therefore, this study will be impactful by contributing to a more comprehensive understanding of collective cell migration, the mechanisms underlying organogenesis, as well as the cell migration and survival programs implicated in normal development and cancer.