Premium
Essential function of p300 acetyltransferase activity in heart, lung and small intestine formation
Author(s) -
Shikama Noriko,
Lutz Werner,
Kretzschmar Ralph,
Sauter Nadine,
Roth JeanneFrançoise,
Marino Silvia,
Wittwer Jonas,
Scheidweiler Alexander,
Eckner Richard
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg502
Subject(s) - biology , null allele , mutant , heterozygote advantage , allele , wild type , microbiology and biotechnology , downregulation and upregulation , acetyltransferase , embryonic stem cell , morphogenesis , genetics , gene , acetylation
p300 and CBP are large nuclear acetyltransferases exhibiting a complex multi‐domain structure. Mouse embryos nullizygous for either p300 or Cbp die at midgestation, while heterozygotes are viable but in part display defects in neurulation or bone morphogenesis. To directly examine the contribution of the acetyltransferase (AT) activity to mouse development, we have abrogated this function by a knock‐in approach. Remarkably, a single AT‐deficient allele of p300 or Cbp leads to embryonic or neonatal lethality, indicating that the mutant alleles are dominant. Formation of the cardiovascular system, the lung and the small intestine are strongly impaired in p300 AT and to a much lesser extent in Cbp AT mutant embryos, a difference that is also reflected by the defects in gene expression. Embryonic stem cells homozygous for either the p300 AT or a p300 null mutation respond differently to BMP2 stimulation, indicating that the two alleles are not equivalent. Unexpectedly, the p300 AT‐mutant cells upregulate BMP‐inducible genes to levels similar or even higher than observed in wild‐type cells.