Roles of uroplakins in plaque formation, umbrella cell enlargement, and urinary tract diseases

• Published in: The Journal of cell biology Vol. 167; no. 6; pp. 1195 - 1204
• Main Authors: Kong, Xiang-Tian, Deng, Fang-Ming, Hu, Ping, Liang, Feng-Xia, Zhou, Ge, Auerbach, Anna B, Genieser, Nancy, Nelson, Peter K, Robbins, Edith S, Shapiro, Ellen, Kachar, Bechara, Sun, Tung-Tien
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 20.12.2004; The Rockefeller University Press
• Subjects: Animals; B lymphocytes; Cell lines; Cellular biology; Epithelium; Genetic Predisposition to Disease; Genetics; Hydronephrosis; Kidney Diseases - genetics; Kidney Diseases - pathology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Knockout; Phenotype; Umbrellas; Ureter; Urinary bladder; Urination; Urologic Diseases - genetics; Urologic Diseases - metabolism; Urologic Diseases - pathology; Uroplakin II; Uroplakin III; Urothelium; Urothelium - cytology; Urothelium - pathology; Urothelium - physiology; Vesico-Ureteral Reflux - metabolism; Water pressure
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200406025

The apical surface of mouse urothelium is covered by two-dimensional crystals (plaques) of uroplakin (UP) particles. To study uroplakin function, we ablated the mouse UPII gene. A comparison of the phenotypes of UPII- and UPIII-deficient mice yielded new insights into the mechanism of plaque formation and some fundamental features of urothelial differentiation. Although UPIII knockout yielded small plaques, UPII knockout abolished plaque formation, indicating that both uroplakin heterodimers (UPIa/II and UPIb/III or IIIb) are required for plaque assembly. Both knockouts had elevated UPIb gene expression, suggesting that this is a general response to defective plaque assembly. Both knockouts also had small superficial cells, suggesting that continued fusion of uroplakin-delivering vesicles with the apical surface may contribute to umbrella cell enlargement. Both knockouts experienced vesicoureteral reflux, hydronephrosis, renal dysfunction, and, in the offspring of some breeding pairs, renal failure and neonatal death. These results highlight the functional importance of uroplakins and establish uroplakin defects as a possible cause of major urinary tract anomalies and death.