title: Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions.
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.
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Fogelgren
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Noemi
authors.initials: N
authors.lastname: Polgar
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Vanessa H
authors.initials: VH
authors.lastname: Lui
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Kadee-Kalia A
authors.initials: KK
authors.lastname: Tamashiro
authors.affiliation: Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, United States of America.
authors.forename: Josephine Andrea
authors.initials: JA
authors.lastname: Napoli
authors.affiliation: Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Chad B
authors.initials: CB
authors.lastname: Walton
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America; Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Lipschutz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001002:Anuria / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006869:Hydronephrosis / Q000235:genetics / Q000378:metabolism; D007682:Kidney Pelvis / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014517:Ureteral Obstruction / Q000235:genetics* / Q000378:metabolism; D019459:Urothelium / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C000606329:EXOC5 protein, mouse; D033921:Vesicular Transport Proteins