Morphogenesis is the process whereby simple tissues, such as epithelial sheets, are sculpted into complex organs. Morphogenesis is driven by forces generated by individual cells, which result in changes in cell shape and tissue mechanics. During development, these changes are tightly regulated in space and time 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 includes biochemistry, genetics, cell and developmental biology, physics, and mathematical modeling. As a graduate student in David Drubin's lab at UC Berkeley, I was trained in cell biology, biochemistry, and genetics. Specifically, I gained much experience working with the actin cytoskeleton, which generates mechanical forces in cells. As a postdoctoral fellow in Eric Wieschaus'lab at Princeton University, I have learned Drosophila biology and have begun to develop quantitative and computational skills to analyze the dynamics of multicellular systems. Specifically, I have analyzed apical constriction, a common cell shape change that facilitates epithelial bending and tissue invagination. These complementary research experiences provide me with a unique perspective and a range of technical expertise that I will use in my independent lab to study how the actin cytoskeleton generates forces during development. In the Wieschaus lab, I discovered that apical constriction is driven by pulsed actomyosin contractions, which incrementally constrict the cell. Pulsed contractions are regulated by the transcription factors Twist and Snail, whose human homologues play important roles in cancer cell metastasis. In the current research plan, I propose experiments that will elucidate the mechanisms that regulate pulsed contraction. 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 that control pulsed contractions downstream of the transcription factors Twist and Snail. A second goal will be to determine how mechanical forces transmitted through the tissue regulate cell shape change and cytoskeletal 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 the actin cytoskeleton and the physical interactions between cells in multicellular systems, which will be essential foundations for my future independent lab. The Wieschaus lab is the ideal environment to obtain this training because we are part of the Center for Quantitative Biology at Princeton University. Eric Wieschaus is an excellent mentor who strongly believes in quantifying experimental data and developing quantitative models to explain this data. I also collaborate with a theoretical physicist at Princeton, Matthias Kaschube, who is an expert on quantitative image analysis. Furthermore, Princeton offers a variety of seminars, 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 and modeling, and will increase the quality and impact of my future research. Overall, this experience will help me achieve my goal of running a multidisciplinary lab that performs cutting edge research on morphogenesis.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Transition Award (R00)
Project #
5R00GM089826-03
Application #
8217255
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gindhart, Joseph G
Project Start
2010-01-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$247,531
Indirect Cost
$83,727
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Vasquez, Claudia G; Tworoger, Mike; Martin, Adam C (2014) Dynamic myosin phosphorylation regulates contractile pulses and tissue integrity during epithelial morphogenesis. J Cell Biol 206:435-50
Mason, Frank M; Tworoger, Michael; Martin, Adam C (2013) Apical domain polarization localizes actin-myosin activity to drive ratchet-like apical constriction. Nat Cell Biol 15:926-36
Mason, Frank M; Martin, Adam C (2011) Tuning cell shape change with contractile ratchets. Curr Opin Genet Dev 21:671-9