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1 Department of Pediatrics, Montreal Children's Hospital, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada
2 Department of Pediatrics, Montreal Children's Hospital, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: indra.gupta{at}muhc.mcgill.ca.
RET, a tyrosine kinase receptor essential for kidney development, has recently been shown to be important for the formation of the urinary tract. When RET is overexpressed in the HoxB7/Ret transgenic mouse, kidneys are small and cystic, and in some of the mice, the ureters are grossly dilated. Here we report that the observed ureteral dilatation is associated with the urinary tract abnormality vesico-ureteric reflux (VUR) in which urine flows retrogradely from the bladder to the ureter. Reflux was determined in vitro by injecting methylene blue into the bladders of HoxB7/Ret and wildtype mice. At postnatal day 1, 30 % of HoxB7/Ret mice had VUR compared to 4 % of wildtype mice (P<0.05). The length of the intravesical ureteral tunnel was shorter in HoxB7/Ret mice compared to wildtype mice, on both the right and the left sides (P<0.05), suggesting a basis for the higher incidence of VUR in these mutants. At embryonic day 11, the ureteric bud was found to exit more caudally from the mesonephric duct in HoxB7/Ret mice and this may predispose to VUR (P<0.05). Wildtype and HoxB7/Ret mice were tested for reflux at embryonic day 17 and both showed a high frequency of VUR (59% and 75%, respectively). These results suggest that VUR may occur transiently during normal urinary tract development before the ureter has completed its insertion into the bladder. In the HoxB7/Ret mouse, overexpression of RET appears to delay the maturation of the distal ureter resulting in postnatal VUR. The HoxB7/Ret mouse is thus an important model to examine how vesicoureteric reflux arises during urinary tract development.
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