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

Kong XT, Deng FM, Hu P, Liang FX, Zhou G, Auerbach AB, Genieser N, Nelson PK, Robbins ES, Shapiro E, Kachar B, Sun TT - J. Cell Biol. (2004)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
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.

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The UPII-deficient urothelium had small superficial cells and a particle-free apical surface. The urothelia from age-matched 3-mo-old wild-type (a and c) and UPII-deficient (b and d) mice were examined by scanning EM (a and b) and quick-freeze deep etch transmission EM (c and d). Note the replacement of large surface umbrella cells (U) by small superficial cells (S) (a and b), and the complete absence of the 16-nm particles and urothelial plaques on the apical surface of the UPII-deficient urothelium (d). cyt, cytoplasm; m, membrane; ups, uroplakin particles. Bars: (a and b) 20 μm; (c and d) 0.2 μm.
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fig4: The UPII-deficient urothelium had small superficial cells and a particle-free apical surface. The urothelia from age-matched 3-mo-old wild-type (a and c) and UPII-deficient (b and d) mice were examined by scanning EM (a and b) and quick-freeze deep etch transmission EM (c and d). Note the replacement of large surface umbrella cells (U) by small superficial cells (S) (a and b), and the complete absence of the 16-nm particles and urothelial plaques on the apical surface of the UPII-deficient urothelium (d). cyt, cytoplasm; m, membrane; ups, uroplakin particles. Bars: (a and b) 20 μm; (c and d) 0.2 μm.

Mentions: Unlike normal urothelium, which was covered by large squamous superficial umbrella cells that could be as large as 100 μm in diameter (Fig. 4 a) and were covered by rigid-looking plaques (Figs. 4 c and 5 a), superficial cells of the UPII-deficient urothelium were uniformly small (20–30 μm; Fig. 4 b) and were completely devoid of the rigid-looking, apical plaques (Fig. 4 d). In addition, the uroplakin-delivering fusiform vesicles (0.7–1 μm in diameter; Fig. 5 a) were totally replaced by numerous small, spherical vesicles (Fig. 5 b). These small vesicles (150–200 nm in diameter) in the UPIII- and UPII-deficient urothelia were moderately and weakly labeled, respectively, by antibodies to uroplakins (Fig. 5, e–h), which indicates that they were involved in delivering the remaining uroplakins to the cell surface. Consistent with these findings, the detergent-insoluble membrane fraction of the UPIII-deficient mouse urothelium showed a significantly reduced number of uroplakins (Fig. 3 k, lanes 3), whereas that of the UPII-deficient urothelium contained almost no detectable uroplakins (Fig. 3 k, lanes 4). Together, these results indicated that UPII ablation completely abolished plaque formation.


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

Kong XT, Deng FM, Hu P, Liang FX, Zhou G, Auerbach AB, Genieser N, Nelson PK, Robbins ES, Shapiro E, Kachar B, Sun TT - J. Cell Biol. (2004)

The UPII-deficient urothelium had small superficial cells and a particle-free apical surface. The urothelia from age-matched 3-mo-old wild-type (a and c) and UPII-deficient (b and d) mice were examined by scanning EM (a and b) and quick-freeze deep etch transmission EM (c and d). Note the replacement of large surface umbrella cells (U) by small superficial cells (S) (a and b), and the complete absence of the 16-nm particles and urothelial plaques on the apical surface of the UPII-deficient urothelium (d). cyt, cytoplasm; m, membrane; ups, uroplakin particles. Bars: (a and b) 20 μm; (c and d) 0.2 μm.
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Related In: Results  -  Collection

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fig4: The UPII-deficient urothelium had small superficial cells and a particle-free apical surface. The urothelia from age-matched 3-mo-old wild-type (a and c) and UPII-deficient (b and d) mice were examined by scanning EM (a and b) and quick-freeze deep etch transmission EM (c and d). Note the replacement of large surface umbrella cells (U) by small superficial cells (S) (a and b), and the complete absence of the 16-nm particles and urothelial plaques on the apical surface of the UPII-deficient urothelium (d). cyt, cytoplasm; m, membrane; ups, uroplakin particles. Bars: (a and b) 20 μm; (c and d) 0.2 μm.
Mentions: Unlike normal urothelium, which was covered by large squamous superficial umbrella cells that could be as large as 100 μm in diameter (Fig. 4 a) and were covered by rigid-looking plaques (Figs. 4 c and 5 a), superficial cells of the UPII-deficient urothelium were uniformly small (20–30 μm; Fig. 4 b) and were completely devoid of the rigid-looking, apical plaques (Fig. 4 d). In addition, the uroplakin-delivering fusiform vesicles (0.7–1 μm in diameter; Fig. 5 a) were totally replaced by numerous small, spherical vesicles (Fig. 5 b). These small vesicles (150–200 nm in diameter) in the UPIII- and UPII-deficient urothelia were moderately and weakly labeled, respectively, by antibodies to uroplakins (Fig. 5, e–h), which indicates that they were involved in delivering the remaining uroplakins to the cell surface. Consistent with these findings, the detergent-insoluble membrane fraction of the UPIII-deficient mouse urothelium showed a significantly reduced number of uroplakins (Fig. 3 k, lanes 3), whereas that of the UPII-deficient urothelium contained almost no detectable uroplakins (Fig. 3 k, lanes 4). Together, these results indicated that UPII ablation completely abolished plaque formation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus