Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model

Rebecca V. Walker (), Jennifer L. Keynton, Daniel T. Grimes, Vrinda Sreekumar, Debbie J. Williams, Chris Esapa, Dongsheng Wu, Martin M. Knight and Dominic P. Norris ()
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Rebecca V. Walker: MRC Harwell Institute
Jennifer L. Keynton: MRC Harwell Institute
Daniel T. Grimes: MRC Harwell Institute
Vrinda Sreekumar: MRC Harwell Institute
Debbie J. Williams: MRC Harwell Institute
Chris Esapa: MRC Harwell Institute
Dongsheng Wu: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London
Martin M. Knight: Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London
Dominic P. Norris: MRC Harwell Institute

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract The human PKD2 locus encodes Polycystin-2 (PC2), a TRPP channel that localises to several distinct cellular compartments, including the cilium. PKD2 mutations cause Autosomal Dominant Polycystic Kidney Disease (ADPKD) and affect many cellular pathways. Data underlining the importance of ciliary PC2 localisation in preventing PKD are limited because PC2 function is ablated throughout the cell in existing model systems. Here, we dissect the ciliary role of PC2 by analysing mice carrying a non-ciliary localising, yet channel-functional, PC2 mutation. Mutants develop embryonic renal cysts that appear indistinguishable from mice completely lacking PC2. Despite not entering the cilium in mutant cells, mutant PC2 accumulates at the ciliary base, forming a ring pattern consistent with distal appendage localisation. This suggests a two-step model of ciliary entry; PC2 first traffics to the cilium base before TOP domain dependent entry. Our results suggest that PC2 localisation to the cilium is necessary to prevent PKD.

Date: 2019
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DOI: 10.1038/s41467-019-12067-y

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