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.

Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos

“…Mice defective for Gcn5 HAT activity survive longer than Gcn5 null mice but still die by E16 and exhibit cranial NTDs (Bu et al, 2007). The Gcn5 flox(neo)/flox(neo) and Gcn5 flox(neo)/⌬ embryos described here survive at least until E18.5 but often suffer exencephaly.…”

“…Our data indicate that decreased expression of Gcn5 does not affect Shh expression or signaling. Normal expression of Shh was observed in Gcn5 hat/hat mutants as well, which also exhibit neural tube closure defects (Bu et al, 2007).…”

“…We have also shown that mouse embryos homozygous for point mutations in Gcn5 that eliminate its acetyltransferase activity exhibit defects in cranial neural tube closure and die by E16.0 (Bu et al, 2007). Here we demonstrate that mice bearing a hypomorphic Gcn5 mutation survive to term with increased incidence of neural tube closure defects and exencephaly.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Among the other families of HATs, the role of Gcn5 in neural development has also been documented, as the acetyltransferase activity and sufficient expression of this enzyme are required for neural tube closure in mice [55,56]. Surprisingly, while p300 HAT mutants exhibit defects in multiple organ systems, the effects of mutating Gcn5 are restricted to the neural tissue, implicating the specificity of Gcn5 acetyltransferase activity, with potential redundancy with PCAF in other tissues [55].…”

“…Surprisingly, while p300 HAT mutants exhibit defects in multiple organ systems, the effects of mutating Gcn5 are restricted to the neural tissue, implicating the specificity of Gcn5 acetyltransferase activity, with potential redundancy with PCAF in other tissues [55]. Gcn5 also plays HATindependent roles during development, and the complete loss of this protein leads to early embryonic lethality after gastrulation [57,58].…”