In normal human populations, nephron number varies widely from 300,000 to over one million nephrons per kidney. This dramatic range was once considered to have no clinical relevance, but recently it has been found that individuals at the lower end of the nephron number spectrum have increased risk of essential hypertension during adulthood. Final nephron number is determined during fetal kidney development and is irreversibly set by birth in humans. The mechanisms which set nephron number remain a mystery. / Humans with the Renal-Coloboma Syndrome (RCS) are born with renal hypoplasia due to a paucity of nephrons. This hereditary disease is caused by mutations in the PAX2 gene, a transcription factor expressed in the kidney, brain and eye. During normal kidney development, PAX2 exerts multiple functions. However, it remains unclear which of these functions is crucial for optimal branching morphogenesis, leading to sufficient nephron formation. Based on our previous observations, we hypothesized that the anti-apoptotic function of PAX2 is critical for determining congenital nephron number. / To test this hypothesis, we used the human PAX2 promoter to target a pro-apoptotic gene (Bax) to the ureteric bud and showed that this was sufficient to cause renal hypoplasia, mimicking RCS. We show that suboptimal fetal branching causes congenital nephron deficits in heterozygous Pax2 mutant mice, which subsequently compromises renal function at one year of age. Furthermore, the nephron deficit in Pax2 mutant mice was rescued by targeting an anti-apoptotic gene (BCL2) to the ureteric bud in fetal kidney. / Finally, we discovered that PAX2 directly activates transcription of the NAIP gene, encoding an endogenous caspase inhibitor first identified in brain. We demonstrate Naip gene expression in developing mouse kidney and show that inhibition of Naip in collecting duct cells causes increased caspase-3/7 activity. / These studies support our hypothesis that the anti-apoptotic function of PAX2 is critical for setting congenital nephron number and we have identified an anti-apoptotic protein, directly regulated by PAX2, which may serve to protect ureteric bud cells from programmed cell death.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111832 |
| Date | January 2005 |
| Creators | Dziarmaga, Alison. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002326146, proquestno: AAINR25136, Theses scanned by UMI/ProQuest. |
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