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Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta
1Institute for Pathology, University of Regensburg Medical School, Germany.
Abstract:
Expression of AP-2 transcription factors has been detected previously in embryonic renal tissues. We show here that AP-2beta -/- mice complete embryonic development and die at postnatal days 1 and 2 because of polycystic kidney disease. Analyses of kidney development revealed that induction of epithelial conversion, mesenchyme condensation, and further glomerular and tubular differentiation occur normally in AP-2beta-deficient mice. At the end of embryonic development expression of bcl-X(L), bcl-w, and bcl-2 is down-regulated in parallel to massive apoptotic death of collecting duct and distal tubular epithelia. Addressing the molecular mechanism we show that transfection of AP-2 into cell lines in vitro strongly suppresses c-myc-induced apoptosis pointing to a function of AP-2 in programming cell survival during embryogenesis. The position of the human AP-2beta gene was identified at chromosome 6p12-p21.1, within a region that has been mapped for autosomal recessive polycystic kidney disease (ARPKD). Sequence analyses of ARPKD patients and linkage analyses using intragenic polymorphic markers indicate that the AP-2beta gene is located in close proximity to but distinct from the ARPKD gene.
Insights
AP-2beta transcription factor deficiency in mice leads to polycystic kidney disease and embryonic lethality due to apoptosis. AP-2beta plays a crucial role in programming cell survival during kidney development.
Area of Science:
- Developmental Biology
- Genetics
- Nephrology
Background:
- AP-2 transcription factors are expressed in embryonic renal tissues.
- Polycystic kidney disease (PKD) is a significant developmental disorder.
Purpose of the Study:
- To investigate the role of AP-2beta in kidney development and its potential link to polycystic kidney disease.
- To elucidate the molecular mechanisms underlying AP-2beta's function in embryonic renal development.
Main Methods:
- Analysis of AP-2beta knockout (AP-2beta -/-) mice.
- Kidney development assessment, including epithelial conversion, mesenchyme condensation, and differentiation.
- Evaluation of apoptosis and expression of apoptosis-related genes (bcl-X(L), bcl-w, bcl-2).
- In vitro transfection studies to assess AP-2's effect on c-myc-induced apoptosis.
- Gene mapping and sequence analysis of the human AP-2beta gene in relation to ARPKD.
Main Results:
- AP-2beta -/- mice exhibit polycystic kidney disease and die postnatally due to massive apoptosis in collecting duct and distal tubular epithelia.
- Kidney development proceeds normally until late embryonic stages, with down-regulation of survival genes preceding apoptosis.
- AP-2 suppresses c-myc-induced apoptosis in vitro, indicating a role in programming cell survival.
- The human AP-2beta gene is located on chromosome 6p12-p21.1, near but distinct from the ARPKD gene.
Conclusions:
- AP-2beta is essential for preventing apoptosis and ensuring cell survival during kidney embryogenesis.
- Dysregulation of AP-2beta function contributes to the pathogenesis of polycystic kidney disease.
- The AP-2beta gene is a potential candidate, though distinct from the primary ARPKD gene, in the etiology of some forms of PKD.