title: Vesico-ureteric reflux and urinary tract development in the Pax2 1Neu+/- mouse.
abstract: 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.
authors: Department of Pediatrics, Montreal Children's Hospital, McGill University, Quebec, Canada.
authors: Inga J
authors: IJ
authors: Murawski
authors: David B
authors: DB
authors: Myburgh
authors: Jack
authors: J
authors: Favor
authors: Indra R
authors: IR
authors: Gupta
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D047108:Embryonic Development; D005260:Female; D015870:Gene Expression; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics; D015994:Incidence; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009929:Organ Size; D051762:PAX2 Transcription Factor / Q000235:genetics*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D017678:Sex Distribution; D014513:Ureter / Q000473:pathology; D001743:Urinary Bladder; D014551:Urinary Tract / Q000002:abnormalities / Q000196:embryology*; D014718:Vesico-Ureteral Reflux / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000097905:Roundabout Proteins
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051762:PAX2 Transcription Factor; D011971:Receptors, Immunologic; C497319:Pax2 protein, mouse; C498888:Robo2 protein, mouse; D000097905:Roundabout Proteins