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Polycystin-2 signalling in Drosophila melanogaster

Subject Area Nephrology
Term from 2008 to 2015
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 58488057
 
Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2. The respective gene products, polycystin-1 and polycystin-2 (TRPP2), function in a common signalling pathway employing Ca2+ as a second messenger. TRPP2 is a Ca2+ -permeable cation channel that forms a complex with polycystin-1. However, it is poorly understood how TRPP2-mediated Ca2+ signals are translated into cellular functions regulating tubular morphology. Notably, the signalling molecules upstream and downstream of TRPP2 are unknown. Therefore, this proposal focuses on: (1) the identification of upstream and downstream components in the polycystin signalling pathway, and (2) the role of TRPP2 in the spatiotemporal regulation of Ca2+ dynamics. We are using Drosophila as a model to genetically dissect the polycystin signalling pathway. Drosophila TRPP2 is a ciliary protein that is expressed in the sperm tail. We found that TRPP2 is required for directed sperm movement in the female reproductive tract. TRPP2 mutant males are sterile because their sperm fail to reach the female sperm storage organs. Since the fundamental mechanisms of polycystin signalling are likely to be evolutionary conserved from flies to humans, we have performed an unbiased forward genetic screen for mutants that phenocopy the TRPP2 mutant phenotype. This screen has revealed novel candidates in the polycystin signalling network in vivo. We will investigate the function of these proteins using a multidisciplinary approach that combines genetic, biochemical, cell biological and live imaging approaches.
DFG Programme Clinical Research Units
 
 

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