Loss of Gcn5 Acetyltransferase Activity Leads to Neural Tube Closure Defects and Exencephaly in Mouse Embryos

Abstract

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.

We thank R. Behringer and members of the Dent lab for helpful discussions. We thank John Latham for reading of the manuscript. We thank Kenneth Dunner for help with scanning electron microscopy of embryos.

Y.A.E. was supported by a Sowell-Huggins Fellowship. This work was supported by a grant from the NIH (GM067718) to S.Y.R.D. DNA sequencing, flow cytometry, and scanning electron microscopy were performed at UTMDACC core facilities supported by the UTMDACC Cancer Center Support Grant (CA16672) from the NCI.