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© The Rockefeller University Press, 0021-9525/2000//961 $5.00
The Journal of Cell Biology, Volume 151, Number 5, , 2000 961-972

Ablation of Uroplakin III Gene Results in Small Urothelial Plaques, Urothelial Leakage, and Vesicoureteral Reflux

^a Epithelial Biology Unit, The Ronald O. Perelman Department of Dermatology, New York, New York 10016
^b Department of Pharmacology, New York, New York 10016
^c Skirball Institute of Biomolecular Medicine, New York, New York 10016
^d Department of Urology, New York, New York 10016
^e Department of Microbiology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016
^f Veterans Administration Medical Center, New York, New York 10010
^g Section on Structural Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892
Department of Dermatology, New York University Medical School, 550 First Avenue, New York, NY 10016.(212) 263-8561(212) 263-5685

Urothelium synthesizes a group of integral membrane proteins called uroplakins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse uroplakin III (UPIII) gene leads to overexpression, defective glycosylation, and abnormal targeting of uroplakin Ib, the presumed partner of UPIII. The UPIII-depleted urothelium features small plaques, becomes leaky, and has enlarged ureteral orifices resulting in the back flow of urine, hydronephrosis, and altered renal function indicators. Thus, UPIII is an integral subunit of the urothelial plaque and contributes to the permeability barrier function of the urothelium, and UPIII deficiency can lead to global anomalies in the urinary tract. The ablation of a single urothelial-specific gene can therefore cause primary vesicoureteral reflux (VUR), a hereditary disease affecting 1% of pregnancies and representing a leading cause of renal failure in infants. The fact that VUR caused by UPIII deletion seems distinct from that caused by the deletion of angiotensin receptor II gene suggests the existence of VUR subtypes. Mutations in multiple gene, including some that are urothelial specific, may therefore cause different subtypes of primary reflux. Studies of VUR in animal models caused by well-defined genetic defects should lead to improved molecular classification, prenatal diagnosis, and therapy of this important hereditary problem.

Key Words: urothelium • permeability • knockout mice • vesicoureteral reflux • hydronephrosis

© 2000 The Rockefeller University Press

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