Mechanisms of epithelial tube fusion

Basic data for this project

Description

Many of our organs, such as the lungs, kidneys, or the vascular system, consist of networks of branched epithelial tubes, which mediate vital functions, such as gas exchange, nutrient transport, and excretion. In case of the vascular system and the kidneys, initially separate units of epithelial tubes fuse to form interconnected tubular networks. The correct pattern of tubular connections is crucial for normal organ function. Aberrant connections of blood vessels can cause vascular pathologies, such as arteriovenous malformations. Despite their medical significance, the cellular and molecular mechanisms that govern epithelial tube fusion are not understood. Only very few studies have addressed this fundamental process during organogenesis, which, owing to experimental limitations, is very difficult to approach in mammals. In the project proposed here, we will use the tracheal (respiratory) system of the fruit fly Drosophila as a model to obtain a mechanistic understanding of epithelial tube fusion at the cellular and molecular level. Tracheal tube fusion in Drosophila involves cell-cell recognition, cell topology changes, de-novo lumen formation, and luminal membrane fusion. The aim of this project is to obtain a comprehensive mechanistic understanding of the tracheal tube fusion process, focusing particularly on lumen formation and membrane fusion events. We propose to address these problems using three complementary approaches. First we will use in vivo single cell labeling techniques combined with high-resolution light microscopy and electron tomography to define the intermediates of the fusion process at the cellular and ultrastructural level. Second, to identify new components of the tube fusion machinery, we will characterize mutations affecting tracheal tube fusion, which we previously isolated in genetic screens. Third, we will explore the role of calcium signaling in tracheal lumen fusion. Answering basic questions about lumen formation and conversion of cellular topology in the Drosophila tracheal tube fusion model will provide a conceptual framework for elucidating similar processes, such as vascular anastomosis and pronephric duct fusion, in more complex vertebrate systems. Since many aspects of epithelial biology, as well as the underlying genes, are conserved, it is likely that principles found in the Drosophila tracheal system pertain to other types of epithelial tubes in various organisms, including humans. In the long run, this knowledge is expected to contribute to the development of novel diagnostic and therapeutic approaches for certain vascular diseases.