PS 12. Uroplakin: discovery and clinical significance

The apical surface of mammalian bladder epithelium is covered by large (500-1000 nm) 2D crystals of hexagonally packed 16- nm uroplakin particles (urothelial plaques). We discovered and characterized the four major uroplakins, UPIa, Ib, II and IIIa, and showed that they are the fundamental building blocks of urothelial plaques. In addition, we showed that uroplakins first form heterodimers of UPIa/II and Ib/IIIa before they can exit from the ER and further polymerize to form heterotetramers six of which then forming a 16-nm particle. Genetic ablation of UPII and UPIIIa abolished plaque formation and diminished urothelial permeability barrier function. We also showed that the high mannose sugars harbored on the large extra extracellular loop of UPIa serves as the urothelial receptor for the type 1-fimbriated E coli that caused 90% of urinary tract infection. Our current research addresses two major areas. In the area of uroplakins, we study how the uroplakins are assembled and targeted to the urothelial apical surface, and define the biological functions and diseases implications of uroplakins. In the area of epithelial stem cells, where we have previously discovered the limbal location of corneal epithelial stem cells and the bulge location of the hair follicular epithelial stem cells, we study the lineage relationships among the urothelial cells covering different segments of the lower urinary tract, and are in the process of identifying and characterizing the urothelial stem cells.