RESEARCH ARTICLE 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 junction ob-structions, and despite their high prevalence, we have a poor understanding of their etiology and scarcity of genetic models. The eight-protein exocyst complex regulates polarized exo-cytosis of intracellular vesicles in a large variety of cell types. Here we report generation of a conditional knockout mouse for Sec10, a central component of the exocyst, which is the first conditional allele for any exocyst gene. Inactivation of Sec10 in ureteric bud-derived cells using Ksp1.3-Cremice resulted in severe bilateral hydronephrosis and complete anuria in newborns, with death occurring 6–14 hours after birth. Sec10FL/FL;Ksp-Cre embryos devel-oped ureteropelvic junction obstructions between E17.5 and E18.5 as a result of degenera-tion of the urothelium and 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 produc-tion of uroplakin proteins that are transported to the apical surface to establish large pla-ques. By E16.5, Sec10FL/FL;Ksp-Cre ureter and pelvic urothelium showed decrease