Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus

• Published in: Experimental & molecular medicine 2018, 50(0), , pp.1-17
• Main Authors: Dafinger, Claudia, Rinschen, Markus M., Borgal, Lori, Ehrenberg, Carolin, Basten, Sander G., Franke, Mareike, Höhne, Martin, Rauh, Manfred, Göbel, Heike, Bloch, Wilhelm, Wunderlich, F. Thomas, Peters, Dorien J. M., Tasche, Dirk, Mishra, Tripti, Habbig, Sandra, Dötsch, Jörg, Müller, Roman-Ulrich, Brüning, Jens C., Persigehl, Thorsten, Giles, Rachel H., Benzing, Thomas, Schermer, Bernhard, Liebau, Max C.
• Format: Article
• Language: English
• Subjects: 13; 14; 14/63; 59; 59/57; 631/45/475/2290; 631/80/304; 64; 64/110; 64/60; 692/699/1585/1589; 82/58; Adenosine triphosphatase; Animals; ATPases Associated with Diverse Cellular Activities - deficiency; Biomedical and Life Sciences; Biomedicine; Cilia; Cilia - genetics; Cilia - metabolism; Ciliopathies - genetics; Ciliopathies - metabolism; Ciliopathies - pathology; Clonal deletion; DNA Helicases - deficiency; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Gene Deletion; Hydrocephalus; Hydrocephalus - genetics; Hydrocephalus - metabolism; Hydrocephalus - pathology; Kidney diseases; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Medical Biochemistry; Mice; Mice, Transgenic; Molecular Medicine; Renal failure; Stem Cells; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0108-z

Ciliopathies comprise a large number of hereditary human diseases and syndromes caused by mutations resulting in dysfunction of either primary or motile cilia. Both types of cilia share a similar architecture. While primary cilia are present on most cell types, expression of motile cilia is limited to specialized tissues utilizing ciliary motility. We characterized protein complexes of ciliopathy proteins and identified the conserved AAA-ATPase Ruvbl1 as a common novel component. Here, we demonstrate that Ruvbl1 is crucial for the development and maintenance of renal tubular epithelium in mice: both constitutive and inducible deletion in tubular epithelial cells result in renal failure with tubular dilatations and fewer ciliated cells. Moreover, inducible deletion of Ruvbl1 in cells carrying motile cilia results in hydrocephalus, suggesting functional relevance in both primary and motile cilia. Cilia of Ruvbl1-negative cells lack crucial proteins, consistent with the concept of Ruvbl1-dependent cytoplasmic pre-assembly of ciliary protein complexes. Cell cilia: Protein crucial for function identified A protein involved in building and maintaining thin protrusions from cell surfaces called cilia is implicated in “ciliopathies”, diseases in which ciliary function is disrupted. These include polycystic kidney disease and disorders collectively known as ciliary dyskinesias. “Primary cilia” perform sensory functions, detecting external chemical and physical signals and initiating responses within cells. In addition, “motile cilia” beat rhythmically to move fluids surrounding cells. Researchers in Germany and the Netherlands, led by Bernhard Schermer and Max C. Liebau at the University of Cologne, studied a protein called Ruvbl1, known to interact with DNA and other proteins. The researchers found it is crucial for the functioning of both types of cilia. Deleting the gene for Ruvbl1 in mice caused kidney failure and a build-up of fluid in the brain known as hydrocephalus. The research could help understand and ultimately treat ciliopathies.