Fibrocystin is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis

• Main Authors: Wolfgang H. Ziegler, Birga Soetje, Lisa P. Marten, Jana Wiese, Mithila Burute, Dieter Haffner
• Format: Article
• Language: English
• Published: MDPI AG 2020-07-01
• Series: International Journal of Molecular Sciences
• Subjects: polycystic kidney disease; fibrocystin; adhesion signaling; epithelial polarity; lumen formation
• Online Access: https://www.mdpi.com/1422-0067/21/14/5140

Mutations of the <i>Pkhd1</i> gene cause autosomal recessive polycystic kidney disease (ARPKD). <i>Pkhd1</i> 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 <i>Pkhd1</i>-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. <i>Pkhd1</i> 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, <i>Pkhd1</i> 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.