Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size

Abstract

Networks of epithelial and endothelial tubes are essential for the function of organs such as the lung, kidney, and vascular system. The sizes and shapes of these tubes are highly regulated to match their individual functions. Defects in tube size can cause debilitating diseases such as polycystic kidney disease (PKD) and ischemia1,2. It is therefore critical to understand how tube dimensions are regulated. Here we identify the tyrosine kinase Src as an instructive regulator of epithelial tube length in the Drosophila tracheal system. Loss-of-function Src42 mutations shorten tracheal tubes while Src42 over-expression elongates them. Surprisingly, Src42 acts distinctly from known tube size pathways and regulates both the amount of apical surface growth and, with the conserved formin dDaam, the direction of growth. Quantitative 3-D image analysis reveals that Src42 and dDaam mutant tracheal cells expand more in the circumferential than the axial dimension, resulting in tubes that are shorter in length – but larger in diameter – than WT tubes. Thus, Src42 and dDaam control tube dimensions by regulating the direction of anisotropic growth, a mechanism that has not previously been described.

Celsr1 is required for the generation of polarity at multiple levels of the mouse oviduct

“…Various morphogenetic events are known to coincide with cellular shape changes (Condic et al, 1991;Taniguchi et al, 2011;Wang et al, 2012), and a few reports suggest that regulation of apical cell shape is required for proper morphogenesis (Nelson et al, 2012;Taniguchi et al, 2011). Although the correlation between PCP signaling and polarized cellular geometries has been shown to be poor in flies (Aigouy et al, 2010;Bosveld et al, 2012), here we report that the geometric characteristics of the cellular apical surface are regulated by the PCP pathway in mouse oviduct epithelium.…”

Luminal matrices: An inside view on organ morphogenesis

“…Oriented cell intercalation, cell division and cell elongation also participate in regulating lumen dimensions during size-maturation of the organ. In the developing Drosophila tracheae, axial tube elongation relies on polarized cell shape changes along the tube axis [4,5], while in Xenopus embryos, the pronephric tubules elongate through rosette-based cell intercalation [6]. The latter is similar to the highly stereotyped cell intercalation events observed during germband elongation in Drosophila [7], and both processes depend on planar cell polarity (PCP) signalling.…”

“…Tracheal tube elongation is controlled independently of diametric expansion and requires the tyrosine kinase Src42 for polarized cell shape changes in the axial dimension of the tubes [4,5]. Src42 could be involved in sensing anisotropic mechanical forces or in translating such mechanical cues into oriented cell elongation by regulating adherens junction remodelling [4] and actin polymerization through effects on the formin DAAM [5].…”

Tubulogenesis

“…Changing the shape and orientation of cells also alters tube size. For example, in the Drosophila tracheal system, mutations in Src42 do not change the rectangular shape of tracheal cells but instead cause cells to expand in the circumferential rather than axial direction of the tube, resulting in shorter but wider tubes (Förster and Luschnig, 2012;Nelson et al, 2012). Mutations in lumenal ECM proteins have been shown to increase the length of tracheal cells and tubes (Araújo et al, 2005;Swanson and Beitel, 2006).…”