Genetic Regulation of Nephron Progenitor Cells in the Mammalian Kidney

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DESCRIPTION (provided by applicant): The basic functional unit of the kidney, the nephron, is generated repetitively during kidney organogenesis. With kidney disease, nephrons are lost and the fibrotic interstitium expands. Although the mammalian kidney can regenerate partially-damaged nephrons, de novo formation of nephrons is not observed. During kidney development, we previously identified the cap mesenchyme as a multipotent self-renewing nephron progenitor population. Our preliminary data suggest that nephron and interstitium form distinct compartments with a distinct lineage boundary. Currently it is unclear how the nephron and interstitial tissues are specified and maintained. Our preliminary data suggest that a transcription factor PAX2 is essential to maintain nephron progenitor cells by repressing trans-differentiation into the interstitium during kidney organogenesis. Thus, Pax2 activity establishes the developmental boundary between the nephron and interstitial lineages during kidney organogenesis. However, how Pax2 activity maintains nephron progenitor cells is unknown. Furthermore, although our data suggest that Pax2 is required to maintain nephron progenitor cells, it remains unclear whether Pax2 activity is sufficient to specify the nephron progenitor status. In this study, we propose to further investigate roles of the Pax2 gene during nephron development. In Aim 1, we will perform detailed molecular analysis of Pax2 functions for nephron progenitor cells. In Aim 2, we will examine whether Pax2 regulates cell adhesion to maintain cap mesenchyme cells. In Aim 3, we will compare Pax2 function before and after the onset of nephron differentiation. Our proposed studies should give better insights into the genetic regulatory mechanisms for nephron progenitor cells, which may lead to development of novel therapeutic paradigms for kidney diseases in humans.