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

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...

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Autores principales: Walker, Rebecca V., Keynton, Jennifer L., Grimes, Daniel T., Sreekumar, Vrinda, Williams, Debbie J., Esapa, Chris, Wu, Dongsheng, Knight, Martin M., Norris, Dominic P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731238/
https://www.ncbi.nlm.nih.gov/pubmed/31492868
http://dx.doi.org/10.1038/s41467-019-12067-y
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author Walker, Rebecca V.
Keynton, Jennifer L.
Grimes, Daniel T.
Sreekumar, Vrinda
Williams, Debbie J.
Esapa, Chris
Wu, Dongsheng
Knight, Martin M.
Norris, Dominic P.
author_facet Walker, Rebecca V.
Keynton, Jennifer L.
Grimes, Daniel T.
Sreekumar, Vrinda
Williams, Debbie J.
Esapa, Chris
Wu, Dongsheng
Knight, Martin M.
Norris, Dominic P.
author_sort Walker, Rebecca V.
collection PubMed
description 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.
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spelling pubmed-67312382019-09-09 Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model Walker, Rebecca V. Keynton, Jennifer L. Grimes, Daniel T. Sreekumar, Vrinda Williams, Debbie J. Esapa, Chris Wu, Dongsheng Knight, Martin M. Norris, Dominic P. Nat Commun Article 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. Nature Publishing Group UK 2019-09-06 /pmc/articles/PMC6731238/ /pubmed/31492868 http://dx.doi.org/10.1038/s41467-019-12067-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Walker, Rebecca V.
Keynton, Jennifer L.
Grimes, Daniel T.
Sreekumar, Vrinda
Williams, Debbie J.
Esapa, Chris
Wu, Dongsheng
Knight, Martin M.
Norris, Dominic P.
Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
title Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
title_full Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
title_fullStr Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
title_full_unstemmed Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
title_short Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
title_sort ciliary exclusion of polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731238/
https://www.ncbi.nlm.nih.gov/pubmed/31492868
http://dx.doi.org/10.1038/s41467-019-12067-y
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