The organizing principles that generate tissue structure are critical to the formation and function of organ systems. A major challenge in developmental biology is to understand how tissue structure is generated on a cellular and molecular level. Cell intercalation is a conserved morphogenetic process involving hundreds of cells that generates one of the striking properties of embryonic form - the body axis. This process is mediated by polarized cell behaviors, but the mechanisms that generate these behaviors are largely unknown. The goal of this proposal is to understand how intercalating cells establish polarity, define the molecular components that translate these polarities into directed cell behavior, and characterize the cell interactions that link these cell behaviors to a transformation in tissue structure. We found that intercalating cells in the Drosophila embryo display an asymmetric distribution of adherens junctions and actin-myosin cables that could directly influence cell movement. To understand how these properties of polarity are established and coordinated, we will define the earliest asymmetries that form in intercalating cells. We hypothesize that the first proteins to localize may direct the organization of other subcellular compartments. To test this hypothesis, we will analyze polarity in mutants defective for specific components. These studies will provide information about the molecular mechanisms that generate cytoarchitecture in intercalating cells. In a forward genetic screen, we identified novel junctional and trafficking proteins that are required for axis elongation in Drosophila. We predict that these proteins govern the polarized localization or activity of junctional proteins that mediate cell interactions important for axis elongation, a prediction we will test by analyzing junctional polarity in mutant embryos. Consistent with this possibility, the behavior of intercalating cells in the Drosophila germband is guided by local cell interactions between cells, although the nature of these interactions is not well-defined. We will combine time-lapse confocal imaging with quantitative approaches from statistical physics and computer science to investigate local cell interactions that generate emergent patterns of cell behavior during tissue elongation. An understanding of the mechanisms that govern cell behavior during normal tissue development may provide insight into the etiology of developmental diseases that affect organ formation. Cell intercalation is essential for neural tube closure, and disruption of this process is responsible for common birth defects. In addition, insight into the dynamic regulation of cell contacts during normal development may shed light on processes of tumor cell metastasis, where misregulation of junctional proteins is a critical step in the progression of epithelial tumors.
Showing the most recent 10 out of 20 publications
