Morphogenesis is the process whereby simple tissues, such as epithelial sheets, are sculpted intocomplex organs. Morphogenesis is driven by forces generated by individual cells, which result in changesin cell shape and tissue mechanics. During development, these changes are tightly regulated in space andtime by both genetic and mechanical signals. During cancer, these signals are often improperly activated,resulting in abnormal cell behavior that leads to tumor cell growth and metastasis. Therefore,understanding how cells and tissues generate forces is essential to understand development and cancer. Because morphogenesis depends on the complex interplay of molecular and mechanical signals,identifying the mechanisms that drive morphogenesis requires a multidisciplinary approach that includesbiochemistry, genetics, cell and developmental biology, physics, and mathematical modeling. As agraduate student in David Drubin's lab at UC Berkeley, I was trained in cell biology, biochemistry, andgenetics. Specifically, I gained much experience working with the actin cytoskeleton, which generatesmechanical forces in cells. As a postdoctoral fellow in Eric Wieschaus' lab at Princeton University, I havelearned Drosophila biology and have begun to develop quantitative and computational skills to analyze thedynamics of multicellular systems. Specifically, I have analyzed apical constriction, a common cell shapechange that facilitates epithelial bending and tissue invagination. These complementary researchexperiences provide me with a unique perspective and a range of technical expertise that I will use in myindependent lab to study how the actin cytoskeleton generates forces during development. In the Wieschaus lab, I discovered that apical constriction is driven by pulsed actomyosincontractions, which incrementally constrict the cell. Pulsed contractions are regulated by the transcriptionfactors Twist and Snail, whose human homologues play important roles in cancer cell metastasis. In thecurrent research plan, I propose experiments that will elucidate the mechanisms that regulate pulsedcontraction. This will be achieved by integrating live-cell imaging, quantitative image analysis, genetics,biochemistry, and mathematical modeling. One goal will be to identify the molecular mechanisms thatcontrol pulsed contractions downstream of the transcription factors Twist and Snail. A second goal will beto determine how mechanical forces transmitted through the tissue regulate cell shape change andcytoskeletal organization during morphogenesis. To accomplish the goals of my proposal, I need additional training in quantitative image analysis,mathematical modeling, and physics. This will allow me to more effectively analyze the dynamics of theactin cytoskeleton and the physical interactions between cells in multicellular systems, which will beessential foundations for my future independent lab. The Wieschaus lab is the ideal environment to obtainthis training because we are part of the Center for Quantitative Biology at Princeton University. EricWieschaus is an excellent mentor who strongly believes in quantifying experimental data and developingquantitative models to explain this data. I also collaborate with a theoretical physicist at Princeton, MatthiasKaschube, who is an expert on quantitative image analysis. Furthermore, Princeton offers a variety ofseminars, classes, and resources that are at my disposal to further my education in quantitative biology.The additional training I obtain at Princeton will greatly improve my skills in quantitative analysis andmodeling, and will increase the quality and impact of my future research. Overall, this experience will helpme achieve my goal of running a multidisciplinary lab that performs cutting edge research onmorphogenesis.
During development and cancer progression, gene expression induces mechanical changes in cells that result in changes in cell shape and tissue architecture. We will investigate the function of two genes that promote cell shape changes during the development of the fruit fly, and whose human homologues are involved in cancer cell metastasis. We will investigate how these genes generate forces in cells and tissues and whether the mechanical forces in a tissue regulate individual cell behavior.
