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Abstract
Precise control of epithelial tube size is critical for organ function, yet the molecular mechanisms remain poorly understood. Here, we examine the roles of cell growth and a highly conserved organ growth regulatory pathway in controlling the dimensions of the Drosophila tracheal (airway) system, a well-characterized system for investigating epithelial tube morphogenesis. We find that tracheal tube-size is regulated in unexpected ways by the transcription factor Yorkie (Yki, homolog of mammalian YAP and TAZ) and the Salvador/Warts/Hippo (SWH) kinase pathway. Yki activity typically promotes cell division, inhibits apoptosis, and can promote cell growth. However, reducing Yki activity in developing embryos increases rather than decreases the length of the major tracheal tubes, the dorsal trunks (DTs). Similarly, reduction of Hippo pathway activity, which antagonizes Yki, shortens tracheal DTs. yki mutations do not alter DT cell volume or cell number, indicating that Yki and the Hippo pathway regulate cell shape and apical surface area, but not volume. Yki does not appear to act through known tracheal pathways of apical extracellular matrix, septate junctions (SJs), basolateral or tubular polarity. Instead, the Hippo pathway and Yki appear to act downstream or in parallel to SJs because a double mutant combination of an upstream Hippo pathway activator, kibra, and the SJ component sinu have the short tracheal phenotype of a kibra mutant. We demonstrate that the critical target of Yki in tube size control is Drosophila Inhibitor of Apoptosis 1 (DIAP1), which in turn antagonizes the Drosophila effector caspase, Ice. Strikingly, there is no change in tracheal cell number in DIAP1 or Ice mutants, thus epithelial tube size regulation defines new non-apoptotic roles for Yki, DIAP1 and Ice.
Highlights
Organs comprised of epithelial tubes that transport gases or fluids are essential to life for most multicellular animals
During later embryonic development, the large dorsal trunk (DT) tubes elongate by changing cell shape and rearranging cell-cell junctions without increasing cell number [8,9]
We found that the dorsal trunks (DTs) of stage 16 yki mutant embryos had a convoluted appearance and were 16% longer than DTs of wildtype (WT) embryos (Figure 1A,B,I; p,0.005)
Summary
Organs comprised of epithelial tubes that transport gases or fluids are essential to life for most multicellular animals. The function of organs, such as the kidneys, lungs and the vascular system is highly dependent on tubes developing to the proper size [1]. The Drosophila tracheal system is an excellent model for studying the complex processes underlying epithelial tube morphogenesis (reviewed in [1,4,5,6,7]). The Drosophila tracheal system serves as a combined pulmonary and vascular system that directly delivers oxygen to tissues through a ramifying network of epithelial tubes. The tracheal system arises from clusters of cells on the surface of the embryo, and these clusters invaginate, undergo one round of cell division and do not divide again. Tracheal cells retain their apical surfaces and organize into lumencontaining branches. Programmed cell death (apoptosis) plays little, if any, role in tracheal morphogenesis as only 1 cell of the ,80 cells in a tracheal metamere (segment) undergoes apoptosis in about half the developing metameres [10]
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