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Vesicoureteral reflux and other urinary tract malformations in mice compound heterozygous for Pax2 and Emx2
Sami K Boualia1, Yaned Gaitan, Inga Murawski
1Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
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.
Insights
Genetic cooperation between Pax2 and Emx2 in mice leads to congenital anomalies of the kidney and urinary tract (CAKUT). This genetic combination causes urinary tract defects, including vesicoureteral reflux, offering insights into human CAKUT.
Area of Science:
- Developmental Biology
- Genetics
- Pediatric Nephrology
Background:
- Congenital anomalies of the kidney and urinary tract (CAKUT) are a leading cause of chronic kidney disease in children.
- CAKUT encompasses various urinary tract defects, such as vesicoureteral reflux and duplex kidneys, which can occur independently or concurrently.
Purpose of the Study:
- To investigate the genetic cooperativity of key urogenital system development regulators in mice.
- To identify novel regulators contributing to CAKUT.
Main Methods:
- Generation and analysis of compound heterozygous mice for Pax2 and Emx2.
- Examination of urinary tract development in embryos and postnatal mice.
- Investigation of gene regulation between Pax2 and Emx2.
Main Results:
- Pax2;Emx2 compound heterozygous mice exhibit a high incidence of CAKUT-like phenotypes, including duplex systems, ureter obstruction, and vesicoureteral reflux.
- Vesicoureteral reflux in these mice occurs at low intravesical pressures, suggesting high sensitivity.
- Defects in ureter budding appear to be the primary cause of anomalies in compound heterozygotes.
- Pax2 is identified as a direct regulator of Emx2 expression in the Wolffian duct.
Conclusions:
- A haploinsufficient combination of Pax2 and Emx2 genes results in a CAKUT-like phenotype in mice.
- These findings highlight the genetic interaction between Pax2 and Emx2 in urogenital development.
- The study provides a potential model for understanding human CAKUT and vesicoureteral reflux, particularly given the chromosomal location of these genes.
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