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The Invs Gene Encodes a Microtubule-Associated Protein

Jens Nürnberger^*, Andreas Kribben^*, Anabelle Opazo Saez^*, Gerd Heusch, Thomas Philipp^* and Carrie L. Phillips

*Department of Nephrology and Hypertension, and Department of Pathophysiology, University of Essen, Essen, Germany; and Indiana University School of Medicine, Division of Nephrology, Department of Medicine, Indianapolis, Indiana.

Corresponding to Dr. Jens Nürnberger, Department of Nephrology and Hypertension, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany. Phone: 49-201-723-3396; Fax: 49-201-723-3855; E-mail: jens.nuernberger{at}uni-essen.de

ABSTRACT. Microtubule networks are important for many vital processes such as mitosis, cell polarity, and differentiation. Ciliary architecture and function closely depend on the microtubule cytoskeleton, and recent studies suggest a role of apical cilia of renal epithelia in the pathogenesis of polycystic kidney disease. This study evaluates the localization, potential interacting partners, and functional aspects of the Invs gene product inversin. Only recently, INVS has been identified as the gene that is mutated in nephronophthisis type 2, an autosomal recessive polycystic kidney disease. Using immunoprecipitation and co-pelleting assays, we show that the Invs gene product inversin forms a stable complex with tubulin in cultured renal epithelial cells. Inversin localizes to several components of the cytoskeleton including ciliary, random, and polarized microtubule pools. During cell divison, inversin is recruited to mitotic spindle fibers. After microtubule depolymerization using colcemid inversin and tubulin staining is no longer characterized by a network pattern but by homogeneous, diffuse distribution. Inversin does not coprecipitate with tubulin after addition of colcemid. After removal of colcemid, inversin immunofluorescence reappears together with tubulin in centrioles. Treatment with the microtubule stabilizing agent paclitaxel leads to severe alteration of the microtubule cytoskeleton with bundling and formation of long spindles of tubulin and inversin. In conclusion, inversin is closely associated with the microtubule cytoskeleton, and its spatial distribution is dependent on tubulin polymerization. Hence, altered inversin-tubulin interaction may impair ciliary function and thereby contribute to cyst development in nephronophthisis.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673