Final Report Summary - TUBEREMODELLING (Tubular organ remodelling during development, homeostasis and disease) Remodelling of tubular organs, such as the lungs, kidneys and blood vessels, encompasses changes in both cell number and cell shape that allow the organ to adapt to developmental growth, and hormonal or environmental cues. We are using the Drosophila tracheal system as a model tubular organ to understand remodelling during development, homeostasis and disease. The fly trachea transports gases throughout the body, and thus, it is functionally equivalent to the mammalian lungs and blood vessels. Moreover, the molecular and cellular similarities between the fly trachea and the mammalian tubular organs make the latter an excellent model to study tube formation and remodelling. In my lab at the University of Cyprus we focus on two major goals: 1. The characterization of the signaling network that coordinates proliferation and differentiation of tracheal progenitors during developmental remodelling, and 2. The identification of novel molecules involved in tracheal remodelling during homeostasis and tumorigenesis. To address these questions we are using two systems I developed during my postdoctoral fellowship at Harvard Medical School: a developmental tracheal remodelling system, whereby dedicated tracheal progenitor cells undergo coordinated proliferation, differentiation and migration during development to generate anew the adult gas-transporting system, and an adult tracheal remodelling (tracheogenesis) system that allows us to monitor tube remodelling during intestinal inflammation and tumorigenesis, which is reminiscent of pathologic mammalian angiogenesis. With regards to developmental remodelling, we found that the conserved transcription factor Cut coordinates patterning and growth of tracheal progenitors during development by spatially regulating different target genes depending on its quantity (Pitsouli and Perrimon, 2013). In addition, we found that the spatial graded expression of cut is regulated by the antagonistic positive and negative actions of the Wnt/Wingless and Notch signaling pathways, respectively (Pitsouli and Perrimon, 2013). Recently, we have shown that the PDGFR/VEGFR (PVR) pathway is necessary for developmental remodeling (Ioannou and Pitsouli, unpublished) and we have found that immune genes, usually active in hemocytes (the fly blood cells), control cell proliferation during developmental remodeling of the trachea (Kiliaris and Pitsouli, unpublished). With regards to adult tracheal remodelling, we found that it takes place in response to not only bacterial infections, but also other stressors that induce inflammatory signaling or hypoxia in the intestine and it involves the activation of the transcription factor Hif1a/Sima, the FGF/Branchless and the FGFR/Breathless (Tamamouna, Kux, Charalambous and Pitsouli, unpublished). We also found that the Notch pathway autonomously controls adult intestinal tracheogenesis upon infection potentially by repressing the FGFR/Btl pathway (Theophanous and Pitsouli, unpublished) and we have implemented genomics to identify novel tracheogenesis regulators in intestinal inflammation and cancer (Neophytou, Ignatiou and Pitsouli, unpublished). Understanding the cellular and molecular mechanisms that control developmental, homeostatic and disease-promoted tracheal remodelling in a genetically amenable model system like Drosophila will aid our understanding of tubular organ development as well as anomalies, like developmental dysplasias, polycystic kidney disease and tumor angiogenesis.
