Mdm2 is required for maintenance of the nephrogenic niche.
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.
Department of Pediatrics, Section of Pediatric Nephrology, Tulane University School of Medicine, New Orleans, LA, USA.
Sylvia A
SA
Hilliard
Department of Pediatrics, Section of Pediatric Nephrology, Tulane University School of Medicine, New Orleans, LA, USA.
Xiao
X
Yao
Department of Pediatrics, Section of Pediatric Nephrology, Tulane University School of Medicine, New Orleans, LA, USA. Electronic address: seldahr@tulane.edu.
Samir S
SS
El-Dahr
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D055419:Bone Morphogenetic Protein 7 / Q000096:biosynthesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics; D006657:Histones / Q000096:biosynthesis / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D060850:LIM-Homeodomain Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009399:Nephrons / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D038081:Organogenesis / Q000235:genetics; D051762:PAX2 Transcription Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D060528:Wnt4 Protein / Q000096:biosynthesis
D051017:Apoptosis Regulatory Proteins; D055419:Bone Morphogenetic Protein 7; C102208:Cited1 protein, mouse; D006657:Histones; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C499496:Pax8 protein, mouse; C491254:Sall1 protein, mouse; C497420:Six2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C525820:bmp7 protein, mouse; C475961:gamma-H2AX protein, mouse; D049452:Green Fluorescent Proteins; C075637:amphiphysin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases
Cap mesenchyme; Mdm2; Metanephric kidney; Nephron progenitor cells; p53