A Drosophila model to understand lung disease related regulatory imbalances
JAK/STAT and WNT-Yki/Sd signalling systems are evolutionary highly conserved and are found in almost all metazoan organisms. They play critical roles in maintaining cell homoeostasis and functionality, while being relevant for differentiation of many tissues. In the lung, accumulating evidence has shown that deregulation of the two signalling pathway is causally linked to a number of different, mostly chronic lung diseases such as COPD or asthma. To understand the underlying molecular framework that translates this dysregulated signalling into pathogenic states, I used the fruit fly Drosophila as a model, because the corresponding pathways are present in highly simplified versions. In the first part, I was able to show that a balanced JAK/STAT signalling is necessary to ensure the normal functionality of the airway system (trachea) of Drosophila. I found that JAK/STAT signalling is necessary to prevent apoptosis in the larval airway system and that this signalling pathway is recruited in all airway epithelial cells. Stressful stimuli such as cigarette smoke evoked a strong and regionalized activation of the pathway that was most likely been driven by the concurrently induced pathway ligand Upd2. To understand the effect of chronic JAK/STAT activation, which has been associated with chronic lung diseases, I ectopically activated this pathway in the larval trachea. This intervention caused larval or pupal death and induced massive structural changes in airway epithelial cells. The changes comprise epithelial thickening combined with a narrowing of the air-conducting space and a disruption of the tracheal epicuticular structure. Transcriptomic studies revealed that vesicle-mediated transport processes are highly impaired leading to mislocated junctional proteins. In this study, I also investigated the effects of deregulated JAK/STAT signalling on the progenitor cells in three distinct regions. Considering the different response of the three regions to up-regulated JAK/STAT signalling or/and FGF/FGFR signalling, I supposed the cells in the three regions to be distinct cell types. Interestingly, although the JAK/STAT signalling is induced in these proliferating regions, up-regulating this signalling interfered with cell proliferation. Taken together, in this part, I could show that JAK/STAT signalling is essential in fully functional airway epithelium and that its chronic activation induces massive structural changes that strongly interfere with normal cell- and therewith organ functionality. In the second part, I focused on the WNT-Yki/Sd signalling pathway. Here I could show stressful stimuli such as cigarette smoke can evoke regionalized activation of the pathway as well that GFP tagged Yki translocated into the nucleus upon the heavy smoke. To understand the effect of chronic activation of WNT-Yki/Sd signalling pathway, which possibly disturb the repair in response to cigarette induced injury, I ectopically activated this pathway in the larval trachea as well. Here, I could show that the expression of the constitutively active form of the components in the signalling pathway contributed to a similar phenotype. This phenotype occurs in a specific stage during trachea remodelling which relies on the cell spatial differences in shape, structure and function. Transcriptomic studies revealed the intrinsic changes within the affected cells. One additional feature is an induced expression of Wnts corresponding to the noncanonical WNT signalling pathway in response to activation of WNT-Yki/Sd signalling pathway. In this part, I was able to show that the noncanonical WNT-Yki/Sd signalling interfered with cell differentiation. This result is reminiscent of the inhibition of cell differentiation during emphysematous destruction provoked by noncanonical WNT signalling and implicates that the inhibition of YAP/TAZ (human homolog) as a potential therapy for emphysema in mammals.