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Many organs are composed of epithelial tubes that transport vital fluids. Such tubular organs develop in many different ways and generate tubes of widely varying sizes and structures, but always with the apical epithelial surface lining the lumen. We describe recent progress in several diverse cell culture and genetic models of tube morphogenesis, which suggest apical membrane biogenesis, vesicle fusion, and secretion play central roles in tube formation and growth. We propose a unifying mechanism of tube morphogenesis that has been modified to create tube diversity and describe how defects in the tube size-sensing step can lead to polycystic kidney disease.

Many organs are composed of branched networks of epithelial tubes that transport vital fluids or gases. The proper size and shape of tubes are crucial for their transport function, but the molecular processes that govern tube size and shape are not well understood. Here we show that three genes required for tracheal tube morphogenesis in Drosophila melanogaster encode proteins involved in the synthesis and accumulation of chitin, a polymer of N-acetyl-␤-D-glucosamine that serves as a scaffold in the rigid extracellular matrix of insect cuticle. In all three mutants, developing tracheal tubes bud and extend normally, but the epithelial walls of the tubes do not expand uniformly, and the resultant tubes are grossly misshapen, with constricted and distended regions all along their lengths. The genes are expressed in tracheal cells during the expansion process, and chitin accumulates in the lumen of tubes, forming an expanding cylinder that we propose coordinates the behavior of the surrounding tracheal cells and stabilizes the expanding epithelium. These findings show that chitin regulates epithelial tube morphogenesis, in addition to its classical role protecting mature epithelia.branching morphogenesis ͉ tracheal system ͉ Drosophila ͉ tube shape ͉ mandril M any organs, including the lungs, kidney, liver, and vascular system, are composed of branched networks of epithelial (or endothelial) tubes that transport vital fluids or gases, and the proper size and shape of the tubes are crucial for their transport function. Although there has been progress recently in elucidating the molecular basis of some of the early steps in the development of branched tubular networks, including branch budding and tube formation (1-4), very little is understood about the molecular processes that govern tube size and shape. The Drosophila tracheal (respiratory) system, with its simple cellular structure, an epithelial monolayer without surrounding support cells and accessible development and genetics, provides a valuable model system to address fundamental questions of branching morphogenesis, including how tube size and shape are controlled (5).During development of the Drosophila tracheal system, branches bud sequentially from an epithelial sac consisting of Ϸ80 cells in each hemisegment (6). Two primary branches extend toward and fuse with branches from neighboring segments, forming the dorsal trunk that spans the length of the animal, whereas others extend and ramify on internal tissues. Once the network is established, tubes expand postmitotically to reach their characteristic lengths and diameters (7). A genetic screen identified eight genes required for tube expansion (7), four of which have been cloned (8-11). All four encode claudins or other components of septate junctions, the insect equivalent of vertebrate tight junctions (12, 13). Mutations in seven other septate junction genes also affect tube expansion (9-11, 13, 14), demonstrating that these junctions not only seal the tracheal epithelium but also regulate its size a...

The response of Arabidopsis thaliana etiolated seedlings to the plant hormone ethylene is a conspicuous phenotype known as the triple response. We have identified genes that are required for ethylene perception and responses by isolating mutants that fail to display a triple response in the presence of exogenous ethylene. Five new complementation groups have been identified. Four of these loci, designated ein4, ein5, ein6 and ein7, are insensitive to ethylene. The fifth complementation group, eir1, is defined by a novel class of mutants that have agravitropic and ethylene-insensitive roots. Double-mutant phenotypes have allowed the positioning of these loci in a genetic pathway for ethylene signal transduction. The ethylene-response pathway is defined by the following loci: ETR1, EIN4, CTR1, EIN2, EIN3, EIN5, EIN6, EIN7, EIR1, AUX1 and HLS1. ctr1-1 is epistatic to etr1-3 and ein4, indicating that CTR1 acts after both ETR1 and EIN4 in the ethylene-response pathway. Mutations at the EIN2, EIN3, EIN5, EIN6 and EIN7 loci are all epistatic to the ctr1 seedling phenotype. The EIR1 and AUX1 loci define a root-specific ethylene response that does not require EIN3 or EIN5 gene activity. HLS1 appears to be required for differential cell growth in the apical hook. The EIR1, AUX1 and HLS1 genes may function in the interactions between ethylene and other plant hormones that occur late in the signaling pathway of this simple gas.

Nutritional status improved following treatment with ivacaftor for 48 weeks.

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ObjectivePatients with cystic fibrosis (CF) and mutations associated with residual CFTR chloride transport have improved survival rates compared with those homozygous for the F508del-CFTR mutation. Since little is known about rate of lung function decline in patients with CF and residual function (RF) mutations, we evaluated differences in rates of percent predicted FEV1 (ppFEV1) decline between patients with an RF mutation who were heterozygous for F508del and those who were homozygous for F508del, and whether rates of ppFEV1 decline differed across age groups.MethodsPatients in the US CF Foundation Patient Registry from 2006 to 2014 with an RF mutation heterozygous for F508del were compared with F508del-homozygous patients. Mutations were identified based on clinical or in vitro evidence of residual ion transport. Annual rates of ppFEV1 decline were estimated for patients 6 to 45 years of age with ≥3 ppFEV1 values spanning ≥0.5 years in a randomly chosen 2 year period that began at the first ppFEV1 measurement in the calendar year.ResultsA total of 1242 RF and 11,916 F508del-homozygous patients were included. At the first visit, the RF cohort was older (mean [SD], 23.0 [12.1] vs 18.0 [9.6] years) and had better nutritional status (mean [SD] BMI z score, 0.36 [1.09] vs −0.29 [1.08]). Mean (SD) ppFEV1 differed at the first visit between cohorts (80.4 [24.8] vs 73.4 [26.5]; p<0.001). Annual rate of ppFEV1 decline was estimated at −0.70 (SE, 0.20) in the RF cohort compared with −1.91 (0.05) in the F508del-homozygous cohort (p<0.001). After excluding patients with R117H (n=889), the rate of decline was −1.05 (0.39) ppFEV1 per year (p<0.001 vs F508del). The rate of decline for RF patients was most rapid in the 18 to 24–year age group, −1.38 (0.39), but was still significantly less than the −2.52 (0.09) for F508del-homozygous young adults (p=0.004).ConclusionPatients with CF and an RF mutation have lower rates of lung function decline compared with F508del-homozygous patients. However, patients with an RF mutation still demonstrate progressive lung disease, particularly during young adulthood.Please refer to page A259 for declarations of interest in relation to abstract P255.

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