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Wild-type p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys
L A Godley1, J B Kopp, M Eckhaus
1Varmus Laboratory, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Abstract:
Transgenic mice expressing wild-type murine p53 under the control of the mouse mammary tumor virus long terminal repeat (MMTV LTR) undergo progressive renal failure due to abnormal kidney development. Similar phenotypes are observed in two transgenic lines that express wild-type p53 within the ureteric bud but not in transgenic animals expressing a dominant-negative p53 mutant allele. Defective differentiation of the ureteric bud, as evidenced by altered marker expression during development, accompanies expression of the p53 transgene. At E17.5-18.5, metanephric mesenchymal cells undergo high rates of apoptosis, and fewer cells than normal are converted to tubular epithelium. As a result, p53 transgenic kidneys grow to only half of their expected size and contain about half of the normal number of nephrons, with compensatory hypertrophy of the glomeruli. In this setting, rather than arrest the cell cycle or induce apoptosis directly, abnormally high levels of wild-type p53 appear to alter cellular differentiation in embryonic ureteric buds and cause secondary effects (apoptosis and inefficient conversion to epithelium) in the adjacent undifferentiated mesenchyme.
Insights
Transgenic mice with high p53 levels exhibit abnormal kidney development, leading to renal failure. This occurs because p53 disrupts ureteric bud cell differentiation, impacting kidney formation.
Area of Science:
- Developmental Biology
- Genetics
- Nephrology
Background:
- The p53 protein is a critical tumor suppressor involved in cell cycle regulation and apoptosis.
- Aberrant p53 activity is implicated in various developmental abnormalities and diseases.
- Understanding p53's role in kidney development is crucial for addressing congenital kidney disorders.
Purpose of the Study:
- To investigate the impact of wild-type p53 overexpression on embryonic kidney development in transgenic mice.
- To elucidate the mechanisms by which p53 affects ureteric bud differentiation and subsequent kidney organogenesis.
Main Methods:
- Generation of transgenic mouse models expressing wild-type p53 under the MMTV LTR promoter.
- Analysis of kidney development, cell differentiation markers, and apoptosis rates at embryonic stages.
- Comparison between wild-type p53 and dominant-negative p53 mutant expression in transgenic lines.
Main Results:
- Transgenic mice with wild-type p53 showed progressive renal failure and abnormal kidney development.
- Expression of wild-type p53 in the ureteric bud led to defective ureteric bud differentiation.
- Increased apoptosis in metanephric mesenchymal cells and inefficient conversion to tubular epithelium were observed.
- Kidneys were smaller with fewer nephrons, and glomeruli showed compensatory hypertrophy.
Conclusions:
- High levels of wild-type p53 disrupt embryonic kidney development by altering ureteric bud cell differentiation.
- This leads to secondary effects on the adjacent mesenchyme, including apoptosis and impaired epithelial conversion.
- The findings suggest a novel role for p53 in regulating kidney organogenesis beyond direct cell cycle arrest or apoptosis induction.