Exocyst Dysfunction Leads To Defects In Urothelial Differention In A Novel Mouse Model Of Congenital Ureter Obstructions
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2017-05
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Abstract
The exocyst is an eight protein trafficking complex responsible for polarized
exocytosis of a certain subset of vesicles to the plasma membrane. The exocyst is
present in a large variety of cell types and is involved in many different cellular
processes. The protein, Sec10, has been reported to be a central component of the
exocyst, and loss of this protein leads to inactivation of the entire complex. Here we
show that the exocyst complex is essential for primary cilia formation, epithelial
homeostasis, and cell survival in a cell culture model. We also report generation of a
conditional knockout mouse for Sec10, which is the first conditional allele for any
exocyst gene. Inactivation of Sec10 in ureteric bud derived cells results in severe
bilateral hydronephrosis and complete anuria in newborns, with death occurring 6-14
hours after birth. Sec10 conditional knockout mice develop ureteropelvic junction
obstructions between E17.5 and E18.5 due to failure of urothelial progenitor cells to
differentiate into superficial cells, which are responsible for producing uroplakin plaques
on the luminal surface. These Sec10 knockout urothelial cells undergo cell death by
E17.5 and the urothelial barrier becomes leaky to luminal fluid. Also at E17.5, we
measured increased expression of TGFβ1 and genes associated with myofibroblast
activation, with evidence of stromal remodeling. Our findings support the model that a
defective urothelial barrier allows urine to induce a fibrotic wound healing mechanism,
which may contribute to human prenatal UPJ obstructions.
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exocyst, mouse model, urothelial differentiation
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