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Impaired formation of desmosomal junctions in ADPKD epithelia

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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.

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Acknowledgements

We are grateful to Drs. Kathy Klinger and Thomas Natoli for helpful discussions and comments on this manuscript. We thank AIRG and the GIS-Maladies rares Institute for grant support to BK.

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Authors and Affiliations

  1. Genzyme Corporation, 5 Mountain Road, Framingham, Framingham, MA, 01701-9322, USA

    Ryan J. Russo, Hervé Husson, Nikolay O. Bukanov & Oxana Ibraghimov-Beskrovnaya

  2. INSERM 507 and Department of Nephrology, Hopital Necker, University Paris V, Paris, France

    Dominique Joly & Bertrand Knebelmann

  3. Department of Pathology, Hopital Necker, University Paris V, Paris, France

    Natacha Patey

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  1. Ryan J. Russo
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  2. Hervé Husson
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  3. Dominique Joly
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  4. Nikolay O. Bukanov
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  7. Oxana Ibraghimov-Beskrovnaya
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Correspondence to Oxana Ibraghimov-Beskrovnaya.

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Russo, R.J., Husson, H., Joly, D. et al. Impaired formation of desmosomal junctions in ADPKD epithelia. Histochem Cell Biol 124, 487–497 (2005). https://doi.org/10.1007/s00418-005-0055-3

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