Loss of Gcn5 acetyltransferase activity leads to neural tube closure defects and exencephaly in mouse embryos.
Gcn5 was the first transcription-related histone acetyltransferase (HAT) to be identified. However, the functions of this enzyme in mammalian cells remain poorly defined. Deletion of Gcn5 in mice leads to early embryonic lethality with increased apoptosis in mesodermal lineages. Here we show that deletion of p53 allows Gcn5(-/-) embryos to survive longer, but Gcn5(-/-) p53(-/-) embryos still die in midgestation. Interestingly, embryos homozygous for point mutations in the Gcn5 catalytic domain survive significantly longer than Gcn5(-/-) or Gcn5(-/-) p53(-/-) mice. In contrast to Gcn5(-/-) embryos, Gcn5(hat/hat) embryos do not exhibit increased apoptosis but do exhibit severe cranial neural tube closure defects and exencephaly. Together, our results indicate that Gcn5 has important, HAT-independent functions in early development and that Gcn5 acetyltransferase activity is required for cranial neural tube closure in the mouse.
Bu
Ping
P
Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Evrard
Yvonne A
YA
Lozano
Guillermina
G
Dent
Sharon Y R
SY
D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000196:embryology* / Q000201:enzymology* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D051548:Histone Acetyltransferases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009436:Neural Tube Defects / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D015415:Biomarkers; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor