Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta.
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.
Moser
M
M
Institute for Pathology, University of Regensburg Medical School, Germany.
Pscherer
A
A
Roth
C
C
Becker
J
J
Mücher
G
G
Zerres
K
K
Dixkens
C
C
Weis
J
J
Guay-Woodford
L
L
Buettner
R
R
Fässler
R
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000235:genetics; D004847:Epithelial Cells; D018507:Gene Expression Regulation, Developmental; D016259:Genes, myc / Q000502:physiology; D008040:Genetic Linkage; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics / Q000473:pathology; D015183:Restriction Mapping; D017422:Sequence Analysis, DNA; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; C493677:TFAP2B protein, human; C493669:Tfap2b protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors