title: Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2.
abstract: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2⁺/⁻;Emx2⁺/⁻ mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2⁺/⁻;Emx2⁺/⁻ embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans.
authors: Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
authors: Sami K
authors: SK
authors: Boualia
authors: Yaned
authors: Y
authors: Gaitan
authors: Inga
authors: I
authors: Murawski
authors: Robert
authors: R
authors: Nadon
authors: Indra R
authors: IR
authors: Gupta
authors: Maxime
authors: M
authors: Bouchard
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017124:Conserved Sequence; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D005820:Genetic Testing; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D051379:Mice; D051762:PAX2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014513:Ureter / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D014551:Urinary Tract / Q000002:abnormalities* / Q000196:embryology; D014718:Vesico-Ureteral Reflux / Q000196:embryology / Q000473:pathology*; D014928:Wolffian Ducts / Q000378:metabolism / Q000473:pathology; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D018398:Homeodomain Proteins; D051762:PAX2 Transcription Factor; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C497319:Pax2 protein, mouse