Animal cells are asymmetric, often containing different proteins at distinct areas of the membrane. For example, the cells that line our digestive tract are poised to take in nutrients from one side of the cell and deliver them to the rest of the body at the other side. This proposal examines the activity of the Par complex, a set of proteins responsible for creating and maintaining different regions of animal cell membranes. We are also examining how cellular asymmetries are translated into the complex organization seen in animal tissues and organs. One mechanism for creating structure within tissues is to control the placement of the cells that result from a division. This can occur by positioning the mitotic spindle?the apparatus that separates the chromosomes during division?along a particular axis. We are determining how certain areas of the cell membrane recruit molecular motors that generate forces to rotate the spindle into position and construct organized tissues in the process. In general, our work aims to understand how cells process information to speci?cally target polarity and spindle orientation complexes to the appropriate region of the cell at the right time, activate these complexes once they're localized, and how the activity of these complexes is translated into complex cellular functions. Our goals over the next ?ve years are to identify the molecular interactions that specify polarization of the Par complex in asymmetrically dividing neural stem cells and activate the enzyme activity contained within the complex. In previous work, we determined how the Par complex polarizes its substrates and we are attempting to use this to ?reverse engineer? the identi?cation of new polarized proteins. The premise of this project is that knowledge of new polarized factors will help us understand how Par polarity is translated into function, such as the polarized transport found in the epithelial cells in our digestive system. We are also speci?cally interested in one important polarity output: mitotic spindle orientation. The premise of this project is that animal cells often align their mitotic spindle with the axis of polarity during division. One reason for doing this is that it controls the position of the resulting daughter cells, a feature that is important for the construction and maintenance of complex tissues. Our focus is on a protein that is required to prevent cancer-like over proliferation.
Many cells in our body, such as skin cells that provide a physical barrier to the environment, are polarized and loss of polarity is a hallmark of many diseases, including cancer. In this work, we are investigating a set of two proteins, known as the Par complex, that regulate cellular polarities required for proper development and adult physiology. As the loss of polarity is associated with human disease, improving our understanding of the molecules that control this process will contribute to our knowledge of the mechanisms of disease states. We are also investigating how cell polarity is translated into cellular function. Many animal cells divide with a speci?c orientation, and in many cases they control division orientation by positioning their mitotic spindle, the cellular machine responsible for separating chromosomes during division. Here again, mistakes in this process can lead to disruptions in normal physiology, such as the highly organized architecture normally found in our tissues and organs.