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Disappearance of polycystic kidney disease in revertant c-myc transgenic mice
M Trudel1, N Chrétien, V D'Agati
1Institut de Recherches Cliniques de Montréal, Faculté de Médicine de l'Université de Montréal, Quebec, Canada.
Abstract:
Nineteen SBM transgenic mouse lines specifically expressing the c-myc protooncogene in renal epithelium Transgene expression is completely penetrant, leading to death from renal failure. In the course of continuous breeding of eight transgenic lines, all lines underwent spontaneous transgene mutations characterized by partial deletion and probable rearrangement of the transgene insert. Revertant mice and their progeny have no evidence of renal disease. This constitutes the first report of spontaneous mutations occurring within transgene inserts. The high spontaneous mutation frequency of 10(-2) to 10(-3) greatly exceeds that of naturally occurring mutations and is probably favored by the transgene's multiple tandem insertion. These spontaneous mutations demonstrate that the intact transgene is necessary and sufficient to produce the SBM phenotype. Further, these results implicate deregulation of factor(s) governing epithelial cell proliferation in the pathogenesis of PKD in SBM mice.
Insights
Spontaneous mutations in c-myc transgene inserts caused renal failure in SBM mice. Revertant mice showed no disease, indicating the intact transgene is necessary for Polycystic Kidney Disease (PKD).
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- The c-myc protooncogene plays a critical role in cell proliferation.
- Transgenic mouse models are crucial for studying genetic diseases.
- Polycystic Kidney Disease (PKD) pathogenesis involves complex genetic factors.
Purpose of the Study:
- To investigate spontaneous mutations in SBM transgenic mouse lines expressing c-myc in renal epithelium.
- To determine the role of the intact transgene in the development of renal failure and PKD.
- To explore the mutation frequency and mechanisms within transgene inserts.
Main Methods:
- Generation and breeding of nineteen SBM transgenic mouse lines with c-myc expression in renal epithelium.
- Monitoring of eight transgenic lines for spontaneous transgene mutations during continuous breeding.
- Characterization of transgene mutations, including partial deletion and rearrangement.
- Assessment of renal health and disease evidence in revertant mice and their progeny.
Main Results:
- All eight monitored SBM transgenic lines exhibited spontaneous transgene mutations.
- Mutations involved partial deletion and probable rearrangement of the transgene insert.
- Revertant mice and their offspring showed no signs of renal disease.
- A high spontaneous mutation frequency (10^-2 to 10^-3) was observed, exceeding natural mutation rates.
- The intact transgene was found to be necessary and sufficient for the SBM phenotype.
Conclusions:
- Spontaneous mutations within transgene inserts can occur at a high frequency, potentially favored by multiple tandem insertions.
- The SBM phenotype and subsequent renal failure are directly dependent on the intact c-myc transgene.
- Deregulation of factors controlling epithelial cell proliferation is implicated in the pathogenesis of PKD in SBM mice.