Header Logo

Ciliary disassembly, a modifier of Polycystic Kidney Disease

Collapse Biography 

Collapse Overview 
Collapse abstract
The primary cilium is an antenna-like organelle housing numerous signaling pathways. It is indispensable for human health, as structural defects in primary cilia result in pathological conditions as diverse as kidney cysts and cancer to retinal degeneration and brain malformations. However, within the context of cystic diseases, the role of cilia in cyst formation and/or progression is complex and not well understood. In general, loss of primary cilia induces cystogenesis, but it suppresses cystic growth in mouse models of autosomal dominant polycystic kidney disease (ADPKD). One of the unique features of primary cilia is that they are induced to form when cells stop proliferating and are disassembled when cells start proliferating. Given the increased rate of proliferation in ADPKD, we reasoned that defective ciliary assembly/disassembly rates could be a contributing factor in the rapid cystic growth in ADPKD. Therefore, understanding mechanisms of ciliary assembly/disassembly could help understand cyst progression in ADPKD. Towards this end, we have identified a pathway that involves the FBW7 (or FBXW7) E3 ubiquitin ligase, CDK5, and the centrosomal protein NDE1. We showed that when cells exit the cell cycle, NDE1 is primed for recognition by FBW7 by a phosphorylation step mediated by CDK5. Phosphorylated NDE1 is then targeted for degradation through the Skp1, Cullin 1, FBW7 (SCFFBW7) ubiquitin ligase. Because NDE1 is a negative regulator of ciliary elongation, destruction of NDE1 allows cilia to form and function normally. It was recently shown that NDE1 is part of a large multiprotein complex mediating ciliary disassembly. Therefore, FBW7 seems to support cilia formation and maintenance by keeping in check ectopic ciliary disassembly. New preliminary data show that PKD1 and PKD2, whose gene are inactivated in ADPKD, have an essential role in ciliary disassembly suggesting that, in the setting of ADPKD, defective ciliary disassembly could be a contributing factor to cyst progression. Here, we will test the hypothesis that FBW7- and PKD1/2-mediated signaling pathways function antagonistically in the regulation of ciliary disassembly influencing cyst progression in ADPKD. Specifically, we will determine the mechanisms by which FBW7 regulates ciliary disassembly (Specific Aim 1). We will also determine functional and genetic interactions of FBW7- and PKD1/2-mediated pathways in ciliary disassembly, cyst growth, and cell cycle progression (Specific Aim 2). These studies will further our knowledge on the mechanisms of ciliary disassembly and its role in cyst progression in ADPKD.
Collapse sponsor award id

Collapse Time 
Collapse start date
Collapse end date