Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions
Year: 2015
Type: article
Abstract: Most cases of congenital obstructive nephropathy are the result of ureteropelvic junction obstructions, 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 exocytosis 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-Cre mice resulted in severe bilateral hydronephrosis and complete anuria in newborns, with death occurring 6-14 hours after birth. Sec10 FL/FL;Ksp-Cre embryos developed ureteropelvic junction obstructions between E17.5 and E18.5 as a result of degeneration 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 production of uroplakin proteins that are transported to the apical surface to establish large plaques. By E16.5, Sec10 FL/FL;Ksp-Cre ureter and pelvic urothelium showed decreased uroplakin-3 protein at the luminal surface, and complete absence of uroplakin-3 by E17.5. Affected urothelium at 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 urothelium in ureters, and provides experimental evidence that failure of this urothelial barrier may contribute to human congenital urinary tract obstructions.
Source: PLoS ONE
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: U.S. Department of Veterans Affairs, March of Dimes Foundation, Hawaii Community Foundation, University of Alabama at Birmingham, University of Alabama, Satellite Healthcare, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Institute on Minority Health and Health Disparities
Awards: G1215207371, G1427372443, G1619675495, G2733069588, G283777812, Bioscience Research Infrastructure Development for Grant Enhancement and Success, G3579185629, The Hepato/Renal Fibrocystic Disease Core Center, G448342564, Institute for Biogenesis Research: COBRE, UAB Diabetes Research and Training Center, G5121209461, A novel genetic model for congenital obstructive nephropathy, G584611629, COBRE: Center for Cardiovascular Research, G6136176600, Gene Expression Changes in Early 3D Renal Tubulogenesis, The exocyst in kidney development and cyst formation, Rheumatic Diseases Core Centers (P30), The Exocyst in Synthesis, Cystogenesis and Tubulogenesis, COBRE III: Center for Cardiovascular Research, G9000040708, G9000081061, G9000102579, G9000169993, G9000333407, Comprehensive Cancer Center Support Grant
OpenAlex ID: W1524339949