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

Sylvia Hilliard1, Karam Aboudehen, Xiao Yao

  • 1Tulane University School of Medicine, Department of Pediatrics, Section of Pediatric Nephrology, Orleans, LA 70112, USA.

Developmental Biology
|March 23, 2011
PubMed

Insights

Murine Double Minute-2 (Mdm2) is essential for kidney organogenesis by controlling p53 activity. Conditional deletion of Mdm2 in the ureteric bud causes severe kidney defects, highlighting Mdm2's critical role in renal development.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Murine Double Minute-2 (Mdm2) is a key regulator of p53 tumor suppressor activity.
  • Mdm2 knockout embryos exhibit embryonic lethality due to p53-mediated apoptosis.
  • The specific role of Mdm2 in organogenesis, particularly kidney development, remains largely unknown.

Purpose of the Study:

  • To investigate the function of Mdm2 in kidney development.
  • To determine the necessity of Mdm2 in ureteric bud (UB) epithelial cells during renal organogenesis.
  • To elucidate the molecular mechanisms underlying Mdm2's role in kidney formation.

Main Methods:

  • Conditional deletion of the Mdm2 gene in UB epithelial cells of mice (UB(mdm2-/-)).
  • Analysis of kidney morphology, UB branching, and nephrogenic zone development in mutant mice.
  • Ex vivo culture of UB explants to assess developmental defects.
  • Examination of cell proliferation, apoptosis, and gene expression (c-ret, Wnt11, Wnt9b, Lhx-1, Pax-2) in UB(mdm2-/-) cells.
  • Genetic rescue experiments involving p53 deletion in UB(mdm2-/-) mice.

Main Results:

  • UB(mdm2-/-) mice exhibit severe renal hypodysplasia with defective UB branching and an underdeveloped nephrogenic zone.
  • Ex vivo cultured UB(mdm2-/-) explants show arrested development and reduced nephron progenitor formation.
  • UB(mdm2-/-) cells display decreased proliferation and increased apoptosis.
  • Key developmental gene expression (Wnt9b, Lhx-1, Pax-2) is reduced in UB(mdm2-/-) mutant kidneys.
  • The observed renal defects are rescued by concurrent deletion of the p53 gene, indicating p53-mediated pathology.

Conclusions:

  • Mdm2 plays a critical and cell-autonomous role in the ureteric bud lineage during kidney development.
  • Mdm2-mediated inhibition of p53 activity is essential for normal renal organogenesis.
  • Disruption of Mdm2 function leads to kidney hypodysplasia through aberrant p53 signaling.

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