Grant: Project Grant

In recent years, we have shown that proteins called LAR-family phosphatases are necessary for the normal maturation of the connection between the ureter and the bladder. When these genes are inactivated in the mouse, urine is produced but the obstruction between the ureter and the bladder prevents it from reaching the bladder, which results in severe renal damage. We found that this defect occurs because a group of cells should be eliminated to allow for the ureter-bladder connection but in mouse embryos mutant for the phosphatases, these cell are not eliminated correctly. Hence, LAR-family phosphatases are necessary for a form of cellular suicide called programmed cell death (or apoptosis). We have now identified that LAR phosphatases regulate cell death through Inhibitor of Apoptosis Proteins (IAPs) and obtained evidence that this pathway may be also be involved in malformations of the urogenital system. In this proposal, we layout our plan to elucidate precisely how LAR-phosphatases, tyrosine kinases and IAPs regulate apoptosis. We will explore the role of dead cell removal in tissue formation and will further determine whether the regulators of programmed cell death we identified in the mouse are responsible for developmental defects in humans. For this, we established a collaboration with a pediatric nephrologist who collected the DNA from patients suffering from ureter-bladder connection problems. Using this DNA we found that some of these patients seem to carry mutations in the programmed cell death pathway we identified. We will characterize further these mutations and validate them in mouse models. In addition to shed light on the newly identified link between LAR-phosphatases and programmed cell death, these results will impact our understanding of renal malformations in newborns and help physicians determine the best course of action to ureter-bladder connection defects with the least stress and invasive procedures for children.