Patterning and morphogenesis during Drosophila oogenesis

The development of multicellular organisms relies on a small set of construction techniques---assembly, sculpting, and folding (Chapter 1). The genes and mechanisms involved in mediating these processes are well conserved across tissues and species. Therefore, the quantitative analysis of animal development has great potential to inspire completely novel methods for creating synthetic organs and treating degenerative tissue diseases. Using genetics, imaging, and computational analysis, this study has focused on: (1) deciphering the spatial "code" of morphogenesis, and (2) assigning the functions of regulatory subcircuits that control the patterning of epithelial tissues. We chose Drosophila oogenesis as an accessible model system for studying the formation of tubular structures from a 2D epithelial sheet.Parsing the grammar of epithelial morphogenesis. First, we have investigated the regulation and function of potential effectors of morphogenesis, which control the patterning of cellular properties (mechanics and motility) of epithelial sheets. Toward this end, we performed a screen for the expression patterns of cadherins, which are Ca+-dependent cell adhesion molecules. Chapter 2 discusses the expression patterns of differentially expressed cadherins during oogenesis. The diversity of patterns suggests that a "combinatorial code" of cadherin expression may play a role in segregating several cell sub-populations. In chapter 3, we discuss the function and regulation of one of the patterned cadherins, Cad74A. Ectopic expression of Cad74A in two groups of cells normally lacking Cad74A severely disrupts the formation of epithelial tubes, showing that the differential expression pattern of Cad74A plays a role in morphogenesis.Quantitative analysis of pattern formation and gene regulatory networks. In chapter 4, we have characterized the function of multiple negative feedback loops, which provide spatial control over the specification of cells that will transform a 2D sheet into 3D structures. This work provides the first quantitative analysis of multiple EGFR inhibitors during Drosophila oogenesis and is an example of how control theory can be applied to understand gene regulation. The further quantitative analysis into the patterning effects of multiple inhibitors during Drosophila oogenesis can serve as a natural paradigm for developing heuristics for combination therapies which modulate signaling pathways at multiple points and understanding how signaling gradients are interpreted.