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Molecular Control of Polarized Cell Behavior
Summary: Jennifer Zallen is studying the mechanisms by which cell shape and behavior are organized in large cell populations to build the characteristic features of tissues and organs.
A major challenge in developmental biology is to understand how large-scale changes in tissue structure are generated on a cellular and molecular level. Two decades of research in molecular genetics have provided insight into the mechanisms that control cell fate and patterning, but the morphogenetic events that translate cell fate decisions into the shapes of cells and tissues are poorly understood. In my laboratory we address this question through the study of convergent extension, an evolutionarily conserved morphogenetic event involving hundreds of cells that generates a prominent feature of embryonic form—the body axis. We use cell biological, live imaging, and classical genetic approaches in Drosophila to understand how tissue architecture is established and remodeled during development.
In Drosophila, polarized cell movements cause the embryo to more than double in length from head to tail and simultaneously narrow in width from back to front, creating the basic layout of the body plan (Figure 1). This process is characterized by a striking directionality in which large populations of cells align their movement along a common axis. Taking place in an intact epithelium, these cell rearrangements also require the assembly and disassembly of adhesive contacts between cells. We found that proteins involved in actomyosin contraction and cell-cell adhesion are asymmetrically localized in intercalating cells, where they participate directly in polarized cell behavior. A polarized contractile network provides the global spatial cue that guides cell movement, while differential adhesion regulates dynamic interactions between cells.
To understand the molecular and cellular basis of tissue remodeling during axis elongation, we combine live imaging of cell behavior with quantitative approaches from statistical physics and computer science. These studies revealed that intercalating cells organize into multicellular rosette structures that form and resolve in a directional fashion, contributing positively to elongation (Figure 2). A majority of intercalating cells participate in rosette behaviors, which are reiterated throughout the epithelial sheet (Movie). Rosette structures are also present in other tissues that elongate in vertebrates, indicating that these behaviors may represent a general mechanism linking single-cell asymmetries to global tissue reorganization.
These organized patterns of cell behavior reveal that signals communicated between cells, either biochemical or mechanical in nature, act to coordinate cell movements during axis elongation. Intercalating cells rapidly join one rosette after another, indicating that cells can maintain their direction despite changes in their immediate environment. To understand the mechanisms that generate these cell behaviors, we are performing large-scale genetic screens to identify genes involved in axis elongation. Forward genetic screens provide our best strategy to uncover the molecular machinery that mediates tissue morphogenesis, a largely uncharacterized area of developmental biology. Drosophila is an ideal system for this approach because of the extensive molecular genetic tools that are available, the simple morphology of the embryo, and the fact that subtle defects in cell behavior can readily be detected by an overall change in the shape of the embryo. Using a mosaic strategy and a collection of molecularly tagged mutations, we have identified several new genes that are required for axis elongation. The characterization of these genes will provide information about the mechanisms that shape cell and tissue structure.
We are also using computational, biophysical, and time-lapse imaging approaches to understand how genes encode the forces that generate tissue structure. Toward this goal, we are developing computational approaches for the quantitative and high-throughput analysis of cell behavior in three dimensions. These approaches can be used to systematically identify large-scale patterns of cell behavior, address how these behaviors are integrated to produce elongation, and define the nature of the defects in mutant embryos. The ability to link individual genes with specific properties of cell behavior will provide insight into the molecular mechanisms that control tissue organization and may indicate how the misregulation of these processes leads to birth defects and human disease.
These projects were also supported by a Burroughs Wellcome Fund Career Award in the Biomedical Sciences, a March of Dimes Basil O’Connor Starter Scholar Award, a Searle Scholar Award, a W.M. Keck Foundation Distinguished Young Scholar in Medical Research Award, and a grant from the National Institute of General Medical Sciences.
Last updated September 01, 2009
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