One of the fundamental steps in the formation of most organs is the assembly of cells into epithelial layers; simple epithelial cells share a common polarity, are linked by apical junctions and share a basal basement membrane. Epithelial precursors often arise in different parts of the embryo and must aggregate together, often sorting from other types of cells, to form a primordium. Cells within the primordium must then undergo changes in position or shape to create organ morphology. Some remodeling-specific behaviors of normal epithelia cells, such as the loss of adhesion, are reminiscent of cancer cells, the vast majority of which originate from epithelial cells. We want to understand how epithelial cells sort and rearrange, and are studying this in the digestive tract of the nematode C. elegans. C. elegans provides a simple genetic system for investigating basic problems of cell biology, and has had major impact on our understanding of diverse processes such as apoptosis or RNA-mediated gene inhibition. The digestive tract consists primarily of two epithelial tubes, the pharynx and the intestine; we will use the pharyngeal cells to study how precursor cells sort from other cell types, and use the intestine to study how epithelial cells rearrange during organogenesis. Although the pharyngeal precursors cells normally arise from contiguous cells, we demonstrated that they have sorting potential when mixed with other cell types. We want to study the cell biology of sorting in this model, and identify genes required for sorting. Cells at both ends of the intestinal tube undergo a rotation during morphogenesis; we believe this rotation functions to align the lumen throughout the length of the tube. We discovered that the anterior intestinal cells are guided to their new positions by an UNC-6/netrin signaling pathway. This pathway is best understood for its function in nervous system development, but several recent studies have demonstrated that it is also important for the development of non-neural tissues. We want to determine how this pathway functions to reposition the anterior cells, and to determine how cells at the posterior end rotate. Finally, we want to use the powerful genetics of C. elegans to identify genes required for both kinds of epithelial remodeling.
Most human cancers are derived from epithelial cells, and some traits of cancer cells resemble unregulated behaviors of normal epithelia that remodel during development, growth and wound repair. This project uses the model system C. elegans to identify, and understand the functions of, genes that normally control epithelial formation and remodeling. These studies are expected to provide new insights into normal development, and may provide tools and strategies for controlling transformed epithelial cells.
