A junctional problem of apical proportions: epithelial tube-size control by septate junctions in the Drosophila tracheal system

The size of epithelial tubes is critical for the function of organs such as the lung, kidney and vascular system. However, the molecular mechanisms regulating tube size are largely unknown. Recent work in the Drosophila tracheal system reveals that septate junctions play a previously unsuspected role in tube-size control. Surprisingly, this tube-size function is distinct from the established diffusion barrier function of septate junctions, and involves regulation of cell shape rather than cell number. Possible tube-size functions of septate junctions include patterning of the apical extracellular matrix and regulation of conserved cell polarity genes such as Scribble and Discs Large.

Introduction

Survival of multicellular animals depends on efficient delivery of nutrients and removal of wastes by complex networks of epithelial tubes. The tubes in these networks have highly regulated sizes optimized for the tubes’ individual functions. For example, large-diameter tubes are needed for bulk transport, whereas tubes with fine diameters provide large surface areas for the exchange of materials. Aberrant tube sizes can lead to devastating diseases such as Meckel kidney disease [1], medullary cystic kidney disease [2], polycystic liver disease [3] and polycystic kidney disease (PKD) [4]. PKD is of particular concern because it affects approximately 1 in 800 people, half of whom develop end-stage renal failure. However, because the mechanisms of epithelial tube-size control are poorly understood, there are no effective treatments for PKD or other tube-size disorders, nor are there drugs for therapeutically manipulating tube size. For example, drugs that increase vascular tube-size could potentially be used to treat ischemia, while drugs that block vascular tube growth could potentially be used as anti-cancer agents to restrict the blood supply of growing tumors.

One of the best-characterized systems for investigating epithelial tube morphogenesis is the Drosophila tracheal system, which serves as a combined pulmonary and vascular system that delivers oxygen directly to tissues (reviewed in 5., 6.). The tracheal system forms from sac-like invaginations of the surface ectoderm that are dramatically reshaped into the ramifying network of branches seen in the late-stage embryo (Figure 1a). The stereotyped development of the embryonic tracheal system and the powerful molecular genetic tools available in Drosophila have made the tracheal system an outstanding system for studying branching morphogenesis (reviewed in 5., 6., 7.) and, more recently, tube-size control (reviewed in [8^•]). Initial investigations showed that trachea undergo reproducible changes in tube size during development and mutations in eight genes that caused tracheal tubes to have length or diameter abnormalities were isolated (e.g. Figure 1b,c) [9]. Importantly, these mutations did not alter tracheal cell number, indicating that they directly affected cell shape. Recently, four of those genes have been shown to encode components of pleated septate junctions (SJs), revealing an unexpected role for these cell–cell junctions in tracheal tube-size control.

Insect SJs have a function analogous to vertebrate tight junctions in that they form a diffusion barrier that prevents water and solute exchange across epithelia (reviewed in 10., 11., 12.). The recent discovery that Drosophila claudins localize to and are required for formation of SJs suggests that the barrier functions of septate and tight junctions could have a common biochemical basis and evolutionary origin 13., 14.. However, SJs are not simply the insect homologs of tight junctions. Tight junctions are located apical of adherens junctions, whereas SJs are basal and contain conserved proteins that include the tumor suppressors Scribble (Scrib), Discs Large (Dlg) and Lethal Giant Larvae (Lgl) 15., 16., 17., which also localize to basolateral regions in vertebrate cells (reviewed in 10., 18.•, 19.) (Figure 2, Table 1). In the following sections we discuss what is known about SJ-mediated tube-size control and outline several possible mechanisms for this control.