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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/F1736    most recent 00221.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Murawski, I. J. Articles by Gupta, I. R. Search for Related Content PubMed PubMed Citation Articles by Murawski, I. J. Articles by Gupta, I. R.

Vesico-ureteric reflux and urinary tract development in the Pax2^1Neu+/– mouse

¹Department of Pediatrics and ²Human Genetics, Montreal Children's Hospital, McGill University, Quebec, Canada; and ³GSF National Research Center-Institute of Human Genetics, Neuherberg, Germany

Submitted 11 May 2007 ; accepted in final form 10 September 2007

Vesico-ureteric reflux (VUR) is a urinary tract abnormality that affects roughly one-third of patients with renal-coloboma syndrome, an autosomal dominant condition caused by a mutation in PAX2. Here, we report that a mouse model with an identical mutation, the Pax2^1Neu+/– mouse, has a 30% incidence of VUR. In VUR, urine flows retrogradely from the bladder to the ureter and is associated with urinary tract infections, hypertension, and renal failure. The propensity to reflux in the Pax2^1Neu+/– mouse is correlated with a shortened intravesical ureter that has lost its oblique angle of entry into the bladder wall compared with wild-type mice. Normally, the kidney and urinary tract develop from the ureteric bud, which grows from a predetermined position on the mesonephric duct. In Pax2^1Neu+/– mice, this position is shifted caudally while surrounding metanephric mesenchyme markers remain unaffected. Mutant offspring from crosses between Pax2^1Neu+/– and Hoxb7/GFP^+/– mice have delayed union of the ureter with the bladder and delayed separation of the ureter from the mesonephric duct. These events are not caused by a change in apoptosis within the developing urinary tract. Our results provide the first evidence that VUR may arise from a delay in urinary tract maturation and an explanation for the clinical observation that VUR resolves over time in some affected children.

kidney development; urinary tract maturation; intravesical ureter; ureteric bud