The goal of this project is to understand the mechanisms that control tube formation. Tube formation, the folding of flat epithelial sheets into curved structures, is a basic process in the development of organs such as the lungs, kidneys, heart, neural tube, and gut. The most common permanently disabling birth defects in the U.S. result from errors in the development of tubes. For several decades, we have studied tube formation in developing egg chambers of the fruit fly, Drosophila melanogaster. In the fly ovary, flat patches of cells (subsets of the follicular epithelium surrounding the oocyte) produce a pair of elongated tubes; these tubes synthesize eggshell structures that facilitate gas exchange in the embryo. Our analyses of wild-type flies demonstrate that tube development in the egg chamber is remarkably similar to mammalian neural tube formation, the process that creates the spinal chord. This proposal capitalizes on and continues our previous studies exploring the molecular, cellular, and tissue-level factors that contribute to aberrant tube formation in mutants with open, stunted, or branched tubes. Here we focus on a novel class of growth factors that, when up-regulated, induce aberrant cell migration, thereby creating open tubes. These growth factors, called Imaginal disc growth factors (Idgfs), are related to human chitinase-like proteins (CLPs), which have poorly understood roles in remodeling tissue and are up- regulated in autoimmune disorders and metastasizing tumors. We will investigate this gene family in flies by characterizing the phenotypes of the sextuple knock-out strain. Although most flies die, escapers exhibit defects in three distinct cell migration processes: germ cell migration in the embryo, abdominal histoblast migration in the pupa, and dorsal-appendage tube formation in the ovary. We will use genetic, cell biological, and live-imaging techinques to distinguish between competing hypotheses to explain the underlying molecular mechanisms for how these factors remodel tissue, focusing our efforts initially on tube formation in the ovary. Because very little is known about other components that mediate these proteins' activity, we will flesh out the pathway through a dominant modifer screen followed by functional analysis of the identified interacting genes, including genes that regulate actin dynamics and planar cell polarity. We will explore the role of the Idgfs and their network of interacting components by assessing loss-of-function and gain-of-function phenotypes in another developmental process, that of germ cell migration. Since tube formation is highly conserved between invertebrates and vertebrates, and these novel growth factors are conserved yet poorly understood in any system, our studies will give insight into human development and disease.
During development, coordinated cell movements produce the tissue layers in our bodies and shape our organs. Abnormalities in these processes due to genetic factors can cause sterility or produce birth defects, including the most common permanently disabling birth defect, spina bifida, which affects the neural tube. Mis- regulation of cell migration also facilitates tumor-cell metastasis, which is the major cause of death in cancer patients.
