Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
PublisherNature Publishing Group
MetadataShow full item record
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
- Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations.
- Authors: Freedman BS, Lam AQ, Sundsbak JL, Iatrino R, Su X, Koon SJ, Wu M, Daheron L, Harris PC, Zhou J, Bonventre JV
- Issue date: 2013 Oct
- Regulation of polycystin expression, maturation and trafficking.
- Authors: Hu J, Harris PC
- Issue date: 2020 Aug
- The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus.
- Authors: Ha K, Nobuhara M, Wang Q, Walker RV, Qian F, Schartner C, Cao E, Delling M
- Issue date: 2020 Nov 9
- Regulation of ciliary trafficking of polycystin-2 and the pathogenesis of autosomal dominant polycystic kidney disease.
- Authors: Cai Y, Tang Z
- Issue date: 2010 Feb
- Cyst formation following disruption of intracellular calcium signaling.
- Authors: Kuo IY, DesRochers TM, Kimmerling EP, Nguyen L, Ehrlich BE, Kaplan DL
- Issue date: 2014 Sep 30