Genetic control of epithelial tube size

Animals depend upon epithelial and endothelial tubes to transport gases and liquids in the body, and the sizes of the tubes are critical for their transport function. Tube size must be controlled not only during tube formation but throughout development in order to maintain functionality as the animal grows. For example, the human aorta expands approx. 100-fold between embryonic and adult life to keep pace with increased circulatory demand: the adult aorta has a diameter larger than the entire embryo at the time of its formation. Most fundamental questions about tube size regulation, however, remain unanswered. How are the sizes of tubes specified? How are the sizes and shapes of the constituent cells coordinated to construct tubes of the correct size? How do cells measure the diameter and length of the tubes that they form? What cytoskeletal and extracellular-matrix components are used to form and maintain cells in tubular shapes? How are these components regulated to adjust tube size during development? The Drosophila tracheal (respiratory) system provides a tractable model system for investigating these questions. The tracheal system arises from clusters of ectodermal cells that invaginate to form epithelial sacs from which branches sequentially sprout, extend and interconnect. This creates a ramifying network of approx. 10 4 tubes that transports oxygen throughout the larval body (reviewed by Manning and Krasnow, 1993). Substantial progress has been made in identifying and characterizing the genetic programs governing epithelial sac formation, sprouting and growth of the primary, secondary and terminal branches, and tracheal tube fusion (reviewed by Shilo et al., 1997; Metzger and Krasnow, 1999). Also, branch identity genes that specify differences among primary branches have been characterized (Samakovlis et al., 1996a; Kuhnlein and Schuh, 1996; Vincent et al., 1997; Wappner et al., 1997; Chen et al., 1998). However, little is known about the genetics and cell biology of tracheal tube formation and tube size regulation. Several features of the tracheal system make it an excellent system for investigating the mechanisms of tubulogenesis and tube size control. First, the tubes are simple in structure. They are an epithelial monolayer and hence lack complexities introduced by the multilayer structure of most vertebrate tubes including blood vessels and the bronchial tubes of the lungs. Second, each tube is composed of only a small number of cells, each of which can be followed during development (Samakovlis et al., 1996a). Finally, powerful genetic and genomic approaches can be applied to identify and analyze tubulogenesis genes. Because fundamental mechanisms controlling epithelial tube outgrowth and branching are similar in Drosophilaand vertebrates (Metzger and Krasnow, 1999), it seems likely that other aspects of the process, including tube formation and size regulation will also be conserved. In this report, we describe morphometric, cellular and genetic studies of tracheal tube growth during embryonic and 3271 Development 127, 3271-3282 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV7811