(210d) Systems-Level Analysis of Epithelial Patterning and Morphogenesis: The Control of Cytoskeleton and Adhesion Proteins by Signaling Pathways

The morphogenesis of epithelial tissues can be characterized by the sequential execution of a core set of programmed stereotypical shape changes and cellular movements, which result from the differential expression of cytoskeleton and adhesion proteins. The patterned expression of such effector molecules depends on the integration of multiple signaling pathways. Understanding the logic and cellular mechanisms of morphogenesis requires a systems-level analysis of the epithelial patterning and a functional characterization of differentially expressed adhesion and cytoskeleton proteins. The follicular epithelium in Drosophila egg development (oogenesis) serves as an established model for studying epithelial patterning and morphogenesis, amenable to live imaging and sophisticated genetic perturbations. During Drosophila oogenesis, a two-dimensional follicular epithelium encapsulating the developing egg gives rise to an elaborate three-dimensional eggshell, which includes tubular structures called dorsal appendages that project out from the main body, and act as respirator tubes for the developing embryo.

Egg morphogenesis and dorsal appendage formation have been studied extensively, but few connections have been made between signaling pathways, pattern formation, and the physical implementation of the morphogenetic program in this tissue. In an effort to address the knowledge gap between pattern formation and cell mechanics, we have identified the expression pattern of a set of adhesion and cytoskeleton genes, which are required for proper organogenesis. Further, we have characterized the regulation and function of one of these dynamically regulated adhesion genes, the non-classical cadherin, Cad74A, which is expressed starting in mid-oogenesis in all the columnar follicle cells contacting the oocyte except for two dorsolateral patches. The dorsolateral patches correspond to the cells that form the roof of the dorsal appendages by undergoing apical constriction, cell intercalation, and cell migration. Using an antibody to Cad74A, we show that Cad74A repression in the dorsolateral patches is mediated by high levels of the transcription factor Br, which in turn is regulated by the integration of EGFR and Dpp signaling, the two pathways that are essential for patterning the follicle epithelium. We also report the functional analysis of Cad74A which disrupt cell morphology and robust dorsal appendage formation when expression levels are perturbed. Based on the results of the Cad74A case study, we propose a model for the regulation and integrated function of a group of differentially expressed adhesion and cytoskeleton genes during egg development.