ESR7

The role of DLG1 in regulating ciliary length and signalling capacity of kidney epithelial cells


The polycystins are two large membrane proteins that form a ciliary receptor/channel complex implicated in autosomal dominant polycystic kidney disease (PKD). In nematodes ciliary trafficking of polycystins is regulated by kinesin-3 motors, but whether this is true also in vertebrates is not clear. We recently identified a mammalian ciliary kinesin-3 motor protein (KIF13B) that binds the scaffold protein DLG1, which also localizes to cilia. Kidney-specific deletion of Dlg1 in the mouse causes cilium elongation and renal cyst formation, mimicking PKD phenotypes. ESR7 will investigate how DLG1 regulates ciliary length and composition by analysing cultures of wild type and CRISPR/Cas9-generated Dlg1 mutant kidney epithelial cells using fluorescence microscopy and proximity labelling cilia proteomics. Ciliary cargoes of DLG1/KIF13B will be characterized by immunoprecipitation; cell-based assays and phospho-proteomics will be used to test effects of DLG1/KIF13B on signalling e.g. via PI3K/AKT and mTOR. Proteomics and data analysis will be done in collaboration with P8-EKUT and P11-CellNetworks. In collaboration with P5-OSR, ESR7 will test how DLG1/KIF13B affects cellular levels and ciliary distribution of polycystins, as well as extracellular nutrient sensing and coordination of the intracellular metabolic response.

Partner: University of Copenhagen, Denmark

Supervisor: prof dr L.B. Pedersen