Sinuous and varicose function to organize the septate junction complex and regulate tracheal tube size control
Proper morphogenesis of epithelial tubes is crucial for the function of organs such as the lungs, kidneys and vascular system. However, the molecular and cell biological mechanisms of tubulogenesis remain largely unknown. We are using genetic and molecular approaches in the Drosophila tracheal system to study tubulogenesis. The tracheal system is a network of epithelial tubes that serves as the lungs of the fly, but resembles the vertebrate vascular system because it has a ramifying branching pattern and delivers oxygen directly to target tissues. We have isolated and cloned two genes required for tracheal tube size control. In animals mutant for the genes sinuous or varicose, the early events of tubulogenesis occur normally. However, in late embryogenesis, mutant trachea lengthen abnormally and develop localized diameter defects. We have cloned sinuous and shown that it encodes a Drosophila claudin. Claudins are small four transmembrane domain proteins that form the diffusion barrier in vertebrate tight junctions. In Drosophila, septate junctions form the diffusion barrier between epithelial cells. Sinuous localizes to septate junctions and is required for septate junction organization and barrier function. These results suggest that despite their different subcellular localizations and morphology by EM, septate and tight junctions have some underlying molecular similarities. varicose encodes a previously uncharacterized MAGUK (membrane associated guanylate kinase). Varicose is required for septate junction organization and formation of the epithelial paracellular barrier as assessed by dye diffusion assays and conflict microscopy. In both sinuous and varicose mutants, septate junction proteins such as Coracle, Neurexin, Sinuous, Nrv2 and Discs large are mislocalized and/or have greatly reduced levels. Proteins in the adherens junction and marginal zone do not appear to be affected. varicose appears to have functions in the septate junction not shared by sinuous because the phenotype of a varicose sinuous double mutant phenotype is significantly more severe than sinuous or varicose null mutations. Varicose also appears to regulate tracheal tube size through interactions with the apical ECM
Thesis, Dissertation, English, 2006
Dissertation Abstracts International
2006