Grant: Discovery Grants Program - Individual

The cell surface is the interface between cells and their environment. Interactions at this interface enable cells to generate movement, to assume specific shapes, to carry out specific functions, and to form multicellular structures. It perhaps is not surprising that the major network of structures, the so-called cytoskeleton, that gives cells their shape and allows them to move is related to the cell surface, particularly to regions of the surface involved in forming connections both with neighboring cells and with supporting substrates. The long-term objective of my research program is to explore the interaction between intercellular junctions and the cytoskeleton in cells within the context of tissues, and determine how the two systems function together to generate complex remodeling events in cell layers (epithelia) that line the many tubes and cavities in animals. We are particularly interested in how the cytoskeleton and junctions interact to allow cells to detach from their neighbors and to move through epithelia from one compartment to another, or to be released from the epithelium. Over the next five years we will explore the mechanism by which the cytoskeleton and junctions function both to move developing sperm cells through the seminiferous epithelium of the mammalian testis and to release fully formed sperm cells. In humans, roughly 85 million sperm are released from the epithelium in each testis per day. We will focus our research on unique cytoskeleton-related structures termed tubulobulbar complexes (TCs)' that we propose are sub-cellular machines' that internalize and degrade intact intercellular junctions during the extensive epithelial remodeling events that occur during the production and release of sperm cells. One aspect of our study will be to develop a more complete catalogue of the proteins that form TCs. Another will be to show that the junction eating' function of TCs is necessary for allowing sperm cells in the early stages of their development to move from one region to another within the epithelium. One of the more exciting aspects of our study will be to determine if calcium, a major signaling molecule in cells, is involved in regulating the formation, structure and function of these subcellular machines. Our results have already generated a paradigm shift in how biologists view junction disassembly related to sperm release. Over the next few years we anticipate that our results will generate a similar shift in how biologist view the movement of the next generation of developing sperm cells from one compartment to another in the seminiferous epithelium. Importantly, our studies will provide insight into how the junctions and junction turnover are regulated which may contribute to our understanding of the causes of certain forms of male infertility, and to our identifying putative targets for the development of male contraceptives.