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Mdm2 is required for maintenance of the nephrogenic niche
Sylvia A Hilliard1, Xiao Yao1, Samir S El-Dahr1
1Department of Pediatrics, Section of Pediatric Nephrology, Tulane University School of Medicine, New Orleans, LA, USA.
Abstract:
The balance between nephron progenitor cell (NPC) renewal, survival and differentiation ultimately determines nephron endowment and thus susceptibile to chronic kidney disease and hypertension. Embryos lacking the p53-E3 ubiquitin ligase, Murine double minute 2 (Mdm2), die secondary to p53-mediated apoptosis and growth arrest, demonstrating the absolute requirement of Mdm2 in embryogenesis. Although Mdm2 is required in the maintenance of hematopoietic stem cells, its role in renewal and differentiation of stem/progenitor cells during kidney organogenesis is not well defined. Here we examine the role of the Mdm2-p53 pathway in NPC renewal and fate in mice. The Six2-GFP::Cre(tg/+) mediated inactivation of Mdm2 in the NPC (NPC(Mdm)2(-/-)) results in perinatal lethality. NPC(Mdm)2(-/-) neonates have hypo-dysplastic kidneys, patchy depletion of the nephrogenic zone and pockets of superficially placed, ectopic, well-differentiated proximal tubules. NPC(Mdm2-/-) metanephroi exhibit thinning of the progenitor GFP(+)/Six2(+) population and a marked reduction or loss of progenitor markers Amphiphysin, Cited1, Sall1 and Pax2. This is accompanied by aberrant accumulation of phospho-γH2AX and p53, and elevated apoptosis together with reduced cell proliferation. E13.5-E15.5 NPC(Mdm2-/-) kidneys show reduced expression of Eya1, Pax2 and Bmp7 while the few surviving nephron precursors maintain expression of Wnt4, Lhx1, Pax2, and Pax8. Lineage fate analysis and section immunofluorescence revealed that NPC(Mdm2-/-) kidneys have severely reduced renal parenchyma embedded in an expanded stroma. Six2-GFP::Cre(tg/+); Mdm2(f/f) mice bred into a p53 null background ensures survival of the GFP-positive, self-renewing progenitor mesenchyme and therefore restores normal renal development and postnatal survival of mice. In conclusion, the Mdm2-p53 pathway is essential to the maintenance of the nephron progenitor niche.
Insights
The Murine double minute 2 (Mdm2)-p53 pathway is crucial for maintaining nephron progenitor cells (NPCs) in developing kidneys. Disrupting Mdm2 in NPCs leads to kidney developmental defects and perinatal lethality in mice.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Nephrology
Background:
- Nephron endowment, determined by nephron progenitor cell (NPC) renewal, survival, and differentiation, influences susceptibility to chronic kidney disease and hypertension.
- The p53-E3 ubiquitin ligase, Murine double minute 2 (Mdm2), is essential for embryogenesis, but its role in kidney organogenesis and NPC fate is not well understood.
- While Mdm2 is known to maintain hematopoietic stem cells, its specific function in kidney stem/progenitor cells requires further investigation.
Purpose of the Study:
- To investigate the role of the Mdm2-p53 pathway in the renewal and fate of nephron progenitor cells during kidney development.
- To determine the consequences of Mdm2 inactivation in NPCs on kidney organogenesis and postnatal survival.
- To elucidate the molecular mechanisms underlying Mdm2-dependent NPC maintenance.
Main Methods:
- Utilized Six2-GFP::Cre(tg/+) mice for targeted inactivation of Mdm2 in NPCs (NPC(Mdm)2(-/-)).
- Analyzed kidney morphology, progenitor cell populations (Six2-GFP+), and expression of key developmental markers (Amphiphysin, Cited1, Sall1, Pax2, Eya1, Bmp7, Wnt4, Lhx1, Pax8) in neonates and E13.5-E15.5 embryos.
- Assessed cell proliferation, apoptosis, and DNA damage markers (phospho-γH2AX, p53).
- Conducted lineage fate analysis and section immunofluorescence.
- Generated mice with Mdm2-deficient NPCs on a p53 null background to assess rescue effects.
Main Results:
- NPC(Mdm)2(-/-) mice exhibited perinatal lethality with hypo-dysplastic kidneys, reduced nephrogenic zones, and ectopic proximal tubules.
- NPC inactivation of Mdm2 led to a decrease in the Six2-GFP+ progenitor population and loss of progenitor markers.
- Aberrant accumulation of phospho-γH2AX and p53, elevated apoptosis, and reduced cell proliferation were observed in NPC(Mdm)2(-/-) kidneys.
- Reduced expression of Eya1, Pax2, and Bmp7 was noted, while surviving precursors maintained Wnt4, Lhx1, Pax2, and Pax8.
- Severe reduction in renal parenchyma and expanded stroma were evident in NPC(Mdm)2(-/-) kidneys.
- Mice with Mdm2-deficient NPCs on a p53 null background showed restored renal development and postnatal survival.
Conclusions:
- The Mdm2-p53 pathway is essential for maintaining the nephron progenitor niche during kidney development.
- Mdm2 plays a critical role in NPC renewal, survival, and preventing apoptosis and DNA damage.
- Targeting the Mdm2-p53 pathway offers potential therapeutic avenues for kidney developmental disorders.
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