Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions.

Most cases of congenital obstructive nephropathy are the result of ureteropelvic junctionobstructions, and despite their high prevalence, we have a poor understanding of their etiology and scarcity of genetic models. The eight-protein exocyst complexregulates polarized exocytosis of intracellular vesicles in a large variety of cell types. Here we report generation of a conditional knockout mousefor Sec10, a central component of the exocyst, which is the first conditional allele for any exocystgene. Inactivation of Sec10 in ureteric bud-derived cells using Ksp1.3-Cre mice resulted in severe bilateral hydronephrosisand complete anuriain newborns, with death occurring 6–14 hours after birth. Sec10FL/FL;Ksp-Cre embryos developed ureteropelvic junctionobstructions between E17.5 and E18.5 as a result of degeneration of the urotheliumand subsequent overgrowth by surrounding mesenchymal cells. The urothelial cell layer that lines the urinary tract must maintain a hydrophobic luminal barrier again urine while remaining highly stretchable. This barrier is largely established by production of uroplakin proteins that are transported to the apical surface to establish large plaques. By E16.5, Sec10FL/FL;Ksp-Cre ureter and pelvic urotheliumshowed decreased uroplakin-3 protein at the luminal surface, and complete absence of uroplakin-3 by E17.5. Affected urotheliumat the UPJ showed irregular barriers that exposed the smooth muscle layer to urine, suggesting this may trigger the surrounding mesenchymal cells to overgrow the lumen. Findings from this novel mouse model show Sec10 is critical for the development of the urotheliumin ureters, and provides experimental evidence that failure of this urothelial barrier may contribute to human congenital urinary tract obstructions.