Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
PublisherNature Publishing Group
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AbstractThe 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. Copyright 2019, The Author(s).
SponsorsThis work was supported by awards from the UK Medical Research Council to D.P.N. (MC_U142670370) and M.M.K. (MR/L002876/1) and by the NIDDK sponsored Baltimore Polycystic Kidney Disease Research and Clinical Core Center, P30DK090868 (University of Maryland School of Medicine Division of Nephrology, 655W. Baltimore St., Baltimore, MD 21201).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85071896343&doi=10.1038%2fs41467-019-12067-y&partnerID=40&md5=d5fa1dbad53b8f7c3e2d89a5ca0d785e; http://hdl.handle.net/10713/10896