title: Roles of uroplakins in plaque formation, umbrella cell enlargement, and urinary tract diseases.
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.
authors.affiliation: Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Xiang-Tian
authors.initials: XT
authors.lastname: Kong
authors.forename: Fang-Ming
authors.initials: FM
authors.lastname: Deng
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: Feng-Xia
authors.initials: FX
authors.lastname: Liang
authors.forename: Ge
authors.initials: G
authors.lastname: Zhou
authors.forename: Anna B
authors.initials: AB
authors.lastname: Auerbach
authors.forename: Nancy
authors.initials: N
authors.lastname: Genieser
authors.forename: Peter K
authors.initials: PK
authors.lastname: Nelson
authors.forename: Edith S
authors.initials: ES
authors.lastname: Robbins
authors.forename: Ellen
authors.initials: E
authors.lastname: Shapiro
authors.forename: Bechara
authors.initials: B
authors.lastname: Kachar
authors.forename: Tung-Tien
authors.initials: TT
authors.lastname: Sun
mesh_terms: D000818:Animals; D020022:Genetic Predisposition to Disease; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D014570:Urologic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060170:Uroplakin II; D060171:Uroplakin III; D019459:Urothelium / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D014718:Vesico-Ureteral Reflux / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C554659:Upk2 protein, mouse; D060170:Uroplakin II; D060171:Uroplakin III