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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Aberrant activation of p53 due to loss of MDM2 or MDMX causes early lens dysmorphogenesis

Yiwei Zhang1, Xin Zhang2, Hua Lu1

  • 1Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.

Developmental Biology
|September 30, 2014
PubMed

Insights

The MDM2-MDMX-p53 pathway is crucial for normal lens development. Loss of MDM2 or MDMX in developing lenses causes defects, highlighting their essential roles in regulating p53 and maintaining eye morphogenesis.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • The MDM2-MDMX-p53 pathway is vital for controlling p53 activity during embryogenesis.
  • Understanding this pathway's role in specific organ development, like the lens, is crucial.

Purpose of the Study:

  • To investigate the function of the MDM2-MDMX-p53 pathway in lens development.
  • To determine the roles of MDM2 and MDMX in regulating lens epithelial cell (LEC) proliferation, differentiation, and apoptosis.

Main Methods:

  • Utilized a loxp-Cre system in mice to specifically delete MDM2 or MDMX in lens epithelial cells (LECs) starting at embryonic day 9.5 (E9.5).
  • Analyzed lens development, cell proliferation, and apoptosis in genetically modified mice.
  • Assessed the impact of p53 gene dosage (loss of one or two alleles) on lens defects.

Main Results:

  • Deletion of either MDM2 or MDMX in LECs led to apoptosis and reduced proliferation, causing significant lens developmental defects and aphakia.
  • MDM2 deletion resulted in earlier observable lens defects (E10) compared to MDMX deletion.
  • Complete rescue of lens defects was observed only with the loss of two p53 alleles, not one.

Conclusions:

  • Both MDM2 and MDMX are essential for monitoring p53 activity during lens development.
  • These proteins function, either independently or synergistically, to control p53 and ensure normal lens morphogenesis.
  • The MDM2-MDMX-p53 pathway plays a critical role in maintaining ocular development.
Keywords:
ApoptosisCell proliferationEyesLensLens developmentLens dysmorphogenesisMDM2MDMXp53

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