During embryonic morphogenesis sets of cells actively migrate to reach their final location in the embryo. Disruption of cell migration in human cardiac development results in congenital heart defects and unregulated migration underlies metastatic cancer. During development cells are initially primed for migration by gene regulatory networks (GRNs) that determine cell fate. Directed migration requires the cells to polarize and move in response to guidance cues. However, the connections between GRNs and specific developmental cell behaviors are not well understood. I will use Ciona intestinalis to understand how the cardiac GRN contributes to polarization and migration of the two trunk ventral cells (TVCs) that give rise to the Ciona heart. The TVCs migrate as one pair on each side of the embryo, thus providing the simplest possible model of collective cell migration. The TVCs are highly polarized, with the leader cell generating a broad dynamic leading edge required for migration. Previous studies have shown that the FoxF/FGF/RhoDF GRN controls the ability of the TVCs to migrate and transcriptional profiling data generated from FoxF- and FGF-dominant negative embryos has identified a potential list of FoxF/FGF regulatory targets, among them Rab GTPases, their GEFs and GAPS, and receptor tyrosine kinases (RTKs). My preliminary data suggests that Rab GTPase and RTK activity is required for TVC migration and is regulated by the FoxF/FGF/RhoDF cassette. I hypothesize that the FoxF/FGF/RhoDF migratory cassette regulates polarization and migration of the TVCs through Rab GTPase and RTK activity, which have the potential to form a feedback loop. I will use a candidate genes approach to identify the molecular components regulated by the FoxF/FGF/RhoDF cassette that control TVC polarization and produce directed cell movement. This will generate an integrated model of TVC polarization and connect migratory cell behavior to an upstream GRN. Understanding this connection can potentially identify pathways that may be used as therapeutic targets in metastatic cancers.
How gene regulatory networks induce specific developmental cell behaviors is not well understood. I will use the migration of the two cardiac progenitor cells as a simple two-cell model of collective cell migration to determine how the cardiac gene regulatory network confers the Ciona heart precursor cells with the ability to polarize and migrate. This work will result in an integrated model of the cardiac GRN, cell polarity, and cell migration.
