Tight regulation of p53 activity by Mdm2 is required for ureteric bud growth and branching

Abstract

Mdm2 (Murine Double Minute-2) is required to control cellular p53 activity and protein levels. Mdm2 null embryos die of p53-mediated growth arrest and apoptosis at the peri-implantation stage. Thus, the absolute requirement for Mdm2 in organogenesis is unknown. This study examined the role of Mdm2 in kidney development, an organ which develops via epithelial-mesenchymal interactions and branching morphogenesis. Mdm2 mRNA and protein are expressed in the ureteric bud (UB) epithelium and metanephric mesenchyme (MM) lineages. We report here the results of conditional deletion of Mdm2 from the UB epithelium. UB(mdm2-/-) mice die soon after birth and uniformly display severe renal hypodysplasia due to defective UB branching and underdeveloped nephrogenic zone. Ex vivo cultured UB(mdm2-/-) explants exhibit arrested development of the UB and its branches and consequently develop few nephron progenitors. UB(mdm2-/-) cells have reduced proliferation rate and enhanced apoptosis. Although markedly reduced in number, the UB tips of UB(mdm2-/-)metanephroi continue to express c-ret and Wnt11; however, there was a notable reduction in Wnt9b, Lhx-1 and Pax-2 expression levels. We further show that the UB(mdm2-/-) mutant phenotype is mediated by aberrant p53 activity because it is rescued by UB-specific deletion of the p53 gene. These results demonstrate a critical and cell autonomous role for Mdm2 in the UB lineage. Mdm2-mediated inhibition of p53 activity is a prerequisite for renal organogenesis.