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Mdm4 controls ureteric bud branching via regulation of p53 activity

Sylvia A Hilliard1, Yuwen Li1, Angelina Dixon1

  • 1Tulane University School of Medicine, Department of Pediatrics, Section of Pediatric Nephrology, New Orleans, LA 70112, United States of America.

Mechanisms of Development
|May 29, 2020
PubMed

Insights

Mdm4 is crucial for kidney development. Its loss in the ureteric bud lineage disrupts branching and causes kidney hypodysplasia, but p53 loss rescues these defects.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Mdm2 and Mdm4 antagonism with p53 is essential for development.
  • Mdm2 disruption in the ureteric bud lineage causes renal hypodysplasia.

Purpose of the Study:

  • To investigate the specific role of Mdm4 in murine kidney collecting duct system development.

Main Methods:

  • Hoxb7Cre-driven Mdm4 deletion in the ureteric bud lineage (UbMdm4-/-).
  • Analysis of kidney structure, cell apoptosis, and gene expression.
  • Germline p53 loss in UbMdm4-/- mice.

Main Results:

  • Mdm4 loss disrupted branching morphogenesis and induced apoptosis.
  • UbMdm4-/- kidneys showed dilated tips, hypoplastic medulla, and reduced nephron progenitors.
  • Downregulation of Ret and Wnt signaling pathways observed.
  • Mdm4 deletion upregulated p53 activity and target genes.
  • Germline p53 loss rescued kidney development.

Conclusions:

  • Mdm4 plays a critical, unique role in ureteric bud branching morphogenesis.
  • Mdm4 is essential for collecting duct system development.
  • p53 activation mediates the developmental defects caused by Mdm4 loss.

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