Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300.
The transcriptional coactivator and integrator p300 and its closely related family member CBP mediate multiple, signal-dependent transcriptional events. We have generated mice lacking a functional p300 gene. Animals nullizygous for p300 died between days 9 and 11.5 of gestation, exhibiting defects in neurulation, cell proliferation, and heart development. Cells derived from p300-deficient embryos displayed specific transcriptional defects and proliferated poorly. Surprisingly, p300 heterozygotes also manifested considerable embryonic lethality. Moreover, double heterozygosity for p300 and cbp was invariably associated with embryonic death. Thus, mouse development is exquisitely sensitive to the overall gene dosage of p300 and cbp. Our results provide genetic evidence that a coactivator endowed with histone acetyltransferase activity is essential for mammalian cell proliferation and development.
Yao
T P
TP
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Oh
S P
SP
Fuchs
M
M
Zhou
N D
ND
Ch'ng
L E
LE
Newsome
D
D
Bronson
R T
RT
Li
E
E
Livingston
D M
DM
Eckner
R
R
D000818:Animals; D001921:Brain / Q000002:abnormalities; D022762:CCAAT-Enhancer-Binding Proteins; D002455:Cell Division; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006321:Heart / Q000196:embryology; D006579:Heterozygote; D051548:Histone Acetyltransferases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009436:Neural Tube Defects / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D056921:Nuclear Receptor Coactivator 3; D018168:Receptors, Retinoic Acid / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3