title: Impaired formation of desmosomal junctions in ADPKD epithelia.
abstract: Mutations in polycystin-1 (PC-1) are responsible for autosomal dominant polycystic kidney disease (ADPKD), characterized by formation of fluid-filled tubular cysts. The PC-1 is a multifunctional protein essential for tubular differentiation and maturation found in desmosomal junctions of epithelial cells where its primary function is to mediate cell-cell adhesion. To address the impact of mutated PC-1 on intercellular adhesion, we have analyzed the structure/function of desmosomal junctions in primary cells derived from ADPKD cysts. Primary epithelial cells from normal kidney showed co-localization of PC-1 and desmosomal proteins at cell-cell contacts. A striking difference was seen in ADPKD cells, where PC-1 and desmosomal proteins were lost from the intercellular junction membrane, despite unchanged protein expression levels. Instead, punctate intracellular expression for PC-1 and desmosomal proteins was detected. The N-cadherin, but not E-cadherin was expressed in adherens junctions of ADPKD cells. These data together with co-sedimentation analysis demonstrate that, in the absence of functional PC-1, desmosomal junctions cannot be properly assembled and remain sequestered in cytoplasmic compartments. Taken together, our results demonstrate that PC-1 is crucial for formation of intercellular contacts. We propose that abnormal expression of PC-1 causes disregulation of cellular adhesion complexes leading to increased proliferation, loss of polarity and, ultimately, cystogenesis.
authors.affiliation: Genzyme Corporation, 5 Mountain Road, Framingham, MA 01701-9322, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Russo
authors.forename: Hervé
authors.initials: H
authors.lastname: Husson
authors.forename: Dominique
authors.initials: D
authors.lastname: Joly
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
authors.forename: Natacha
authors.initials: N
authors.lastname: Patey
authors.forename: Bertrand
authors.initials: B
authors.lastname: Knebelmann
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
mesh_terms: D015820:Cadherins / Q000378:metabolism; D051181:Desmosomal Cadherins / Q000235:genetics / Q000378:metabolism; D003896:Desmosomes / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007365:Intercellular Junctions / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D050396:TRPP Cation Channels
chemical_list: D015820:Cadherins; D051181:Desmosomal Cadherins; D011506:Proteins; D050396:TRPP Cation Channels