title: Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease.
abstract: Polycystic kidney disease (PKD) is the most common genetic cause of renal failure in humans. Several proteins that are encoded by genes associated with PKD have recently been identified in primary cilia in renal tubular epithelia. These findings have suggested that abnormalities in cilia formation and function may play a role in the pathogenesis of PKD. To directly determine whether cilia are essential to maintain tubular integrity, we conditionally inactivated KIF3A, a subunit of kinesin-II that is essential for cilia formation, in renal epithelia. Constitutive inactivation of KIF3A produces abnormalities of left-right axis determination and embryonic lethality. Here we show that tissue-specific inactivation of KIF3A in renal tubular epithelial cells results in viable offspring with normal-appearing kidneys at birth. Cysts begin to develop in the kidney at postnatal day 5 and cause renal failure by postnatal day 21. The cyst epithelial cells lack primary cilia and exhibit increased proliferation and apoptosis, apical mislocalization of the epidermal growth factor receptor, increased expression of beta-catenin and c-Myc, and inhibition of p21(CIP1). These results demonstrate that the absence of renal cilia produces both the clinical and cell biological findings associated with PKD. Most generally, the phenotype of Kif3a mutant mice suggests a role for primary cilia in the maintenance of lumen-forming epithelial differentiation.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Fangming
authors.initials: F
authors.lastname: Lin
authors.forename: Thomas
authors.initials: T
authors.lastname: Hiesberger
authors.forename: Kimberly
authors.initials: K
authors.lastname: Cordes
authors.forename: Angus M
authors.initials: AM
authors.lastname: Sinclair
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002923:Cilia / Q000648:ultrastructure; D017931:DNA Primers; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D016547:Kinesins / Q000037:antagonists & inhibitors*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D009124:Muscle Proteins / Q000502:physiology*; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002135:Calcium-Binding Proteins; D017931:DNA Primers; C490202:Kif3a protein, mouse; D009124:Muscle Proteins; C074152:kinesin-II; D016547:Kinesins