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Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis

Mutations of the Pkhd1 gene cause autosomal recessive polycystic kidney disease (ARPKD). Pkhd1 encodes fibrocystin/polyductin (FPC), a ciliary type I membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. Contributions of epithelial cell adhesion and contracti...

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Autores principales: Ziegler, Wolfgang H., Soetje, Birga, Marten, Lisa P., Wiese, Jana, Burute, Mithila, Haffner, Dieter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404311/
https://www.ncbi.nlm.nih.gov/pubmed/32698519
http://dx.doi.org/10.3390/ijms21145140
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author Ziegler, Wolfgang H.
Soetje, Birga
Marten, Lisa P.
Wiese, Jana
Burute, Mithila
Haffner, Dieter
author_facet Ziegler, Wolfgang H.
Soetje, Birga
Marten, Lisa P.
Wiese, Jana
Burute, Mithila
Haffner, Dieter
author_sort Ziegler, Wolfgang H.
collection PubMed
description Mutations of the Pkhd1 gene cause autosomal recessive polycystic kidney disease (ARPKD). Pkhd1 encodes fibrocystin/polyductin (FPC), a ciliary type I membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. Contributions of epithelial cell adhesion and contractility to the disease process are elusive. Here, we link loss of FPC to defective epithelial morphogenesis in 3D cell culture and altered cell contact formation. We study Pkhd1-silenced Madin-Darby Canine Kidney II (MDCKII) cells using an epithelial morphogenesis assay based on micropatterned glass coverslips. The assay allows analysis of cell adhesion, polarity and lumen formation of epithelial spheroids. Pkhd1 silencing critically affects the initial phase of the morphogenesis assay, leading to a reduction of correctly polarized spheroids by two thirds. Defects are characterized by altered cell adhesion and centrosome positioning of FPC-deficient cells in their 1-/2-cell stages. When myosin II inhibitor is applied to reduce cellular tension during the critical early phase of the assay, Pkhd1 silencing no longer inhibits formation of correctly polarized epithelia. We propose that altered sensing and cell interaction of FPC-deficient epithelial cells promote progressive epithelial defects in ARPKD.
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spelling pubmed-74043112020-08-18 Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis Ziegler, Wolfgang H. Soetje, Birga Marten, Lisa P. Wiese, Jana Burute, Mithila Haffner, Dieter Int J Mol Sci Article Mutations of the Pkhd1 gene cause autosomal recessive polycystic kidney disease (ARPKD). Pkhd1 encodes fibrocystin/polyductin (FPC), a ciliary type I membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. Contributions of epithelial cell adhesion and contractility to the disease process are elusive. Here, we link loss of FPC to defective epithelial morphogenesis in 3D cell culture and altered cell contact formation. We study Pkhd1-silenced Madin-Darby Canine Kidney II (MDCKII) cells using an epithelial morphogenesis assay based on micropatterned glass coverslips. The assay allows analysis of cell adhesion, polarity and lumen formation of epithelial spheroids. Pkhd1 silencing critically affects the initial phase of the morphogenesis assay, leading to a reduction of correctly polarized spheroids by two thirds. Defects are characterized by altered cell adhesion and centrosome positioning of FPC-deficient cells in their 1-/2-cell stages. When myosin II inhibitor is applied to reduce cellular tension during the critical early phase of the assay, Pkhd1 silencing no longer inhibits formation of correctly polarized epithelia. We propose that altered sensing and cell interaction of FPC-deficient epithelial cells promote progressive epithelial defects in ARPKD. MDPI 2020-07-20 /pmc/articles/PMC7404311/ /pubmed/32698519 http://dx.doi.org/10.3390/ijms21145140 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ziegler, Wolfgang H.
Soetje, Birga
Marten, Lisa P.
Wiese, Jana
Burute, Mithila
Haffner, Dieter
Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis
title Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis
title_full Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis
title_fullStr Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis
title_full_unstemmed Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis
title_short Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis
title_sort fibrocystin is essential to cellular control of adhesion and epithelial morphogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404311/
https://www.ncbi.nlm.nih.gov/pubmed/32698519
http://dx.doi.org/10.3390/ijms21145140
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